JP2024519215A - CDK2 degraders and their uses - Google Patents

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same. The present invention relates to compounds and methods useful for the regulation of cyclin-dependent kinase 2 ("CDK2") protein by ubiquitination and/or degradation by the compounds according to the present invention. The present invention also provides pharma- ceutically acceptable compositions comprising the compounds of the present invention, and methods of using said compositions in the treatment of various disorders. The present application further relates to targeted degradation of CDK2 or CDK2 and CCNE1 proteins by the use of bifunctional molecules, including bifunctional molecules that bind a cereblon-binding moiety to a ligand that binds to CDK2 or CDK2 and CCNE1.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/185,929, filed May 7, 2021, the entirety of which is incorporated by reference herein.

The present invention relates to compounds and methods useful for the modulation of cyclin-dependent kinase 2 ("CDK2") protein by ubiquitination and/or degradation by compounds according to the invention. The present invention also provides pharma- ceutically acceptable compositions comprising the compounds of the invention, and methods of using said compositions in the treatment of various disorders.

BACKGROUND OF THEINVENTION The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. The UPP is central to many cellular processes and, when deficient or out of balance, leads to the pathogenesis of a variety of diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

There are more than 600 E3 ubiquitin ligases that facilitate the ubiquitination of various proteins in vivo, which are divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. In general, see Li et al. (PLOS One, 2008, 3, 1487) entitled "Genome-wide and functional annotation of human E3 ubiquitin ligases identify MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling."; Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) Title: "New insights into ubiquitin E3 ligase mechanism"; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title: "RING domain E3 ubiquitin ligases."; Spratt et al. (Biochem. 2014, 458, 421-437) entitled "RBR E3 ubiquitin ligases: new structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled "Roles of F-box proteins in cancer."

UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation.Bifunctional compounds consisting of target protein binding ligands and E3 ubiquitin ligase ligands induce proteasome-mediated degradation of selected proteins through recruitment to these E3 ubiquitin ligases and subsequent ubiquitination.These drug-like molecules offer the possibility of temporal control of protein expression. Such compounds, upon addition to cells or administration to animals or humans, can induce inactivation of proteins of interest and may be useful as biochemical reagents and provide new paradigms for the treatment of diseases by eliminating pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46).
There is a continuing need in the art for effective treatment of diseases, particularly cancer. Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases. Upon heterodimerization with regulatory subunits known as cyclins, such as cyclin E1 ("CCNE1"), CDKs become fully activated and regulate key cellular processes, including cell cycle progression and cell division. Uncontrolled proliferation is a hallmark of cancer cells. Dysregulation of CDK activity is associated with aberrant regulation of the cell cycle and is detected in virtually all forms of human cancer. Thus, small molecule therapeutics that affect UPP-mediated protein degradation to target cancer-associated proteins, such as cyclin-dependent kinase 2 ("CDK2") or CDK2 and CCNE1 proteins, hold promise as therapeutic agents. Thus, there remains a need to find compounds that are CDK2 or CDK2 and CCNE1 degraders useful as therapeutic agents.

Li et al. (PLOS One, 2008, 3, 1487) Title: "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling." Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) Title: "New insights into ubiquitin E3 ligase mechanism" Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title: "RING domain E3 ubiquitin ligases." Spratt et al. (Biochem. 2014, 458, 421-437) Title: "RBR E3 ubiquitin ligases: new structures, new insights, new questions." Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) Title: "Roles of F-box proteins in cancer." Crews C, Chemistry & Biology, 2010, 17(6):551-555 Schnekloth J.S. Jr. , Chembiochem, 2005, 6(l): 40-46

SUMMARY OF THE PRESENT DISCLOSURE The present application relates to novel bifunctional compounds that function to recruit CDK2 or CDK2 and CCNE1 proteins to E3 ubiquitin ligase for degradation, as well as methods of their preparation and use. In particular, the present disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of CDK2 or CDK2 and CCNE1, which are then degraded and/or otherwise inhibited by the bifunctional compounds described herein. Also provided are monovalent compounds that find utility as inducers of targeted ubiquitination of CDK2 or CDK2 and CCNE1, which are then degraded and/or otherwise inhibited by the monovalent compounds described herein. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, which are compatible with the degradation/inhibition of CDK2 or CDK2 and CCNE1. Further provided herein are methods of using an effective amount of the compounds described herein for the treatment or amelioration of disease conditions, such as those caused by aberrant CDK2 or CDK2 and CCNE1 activity.

The present application further relates to targeted degradation of CDK2 or CDK2 and CCNE1 proteins through the use of bifunctional molecules, including bifunctional molecules that bind a cereblon-binding moiety to a ligand that binds CDK2 or CDK2 and CCNE1.

またはその薬学的に受容可能な塩を有し、ここで各可変物は、本明細書中で定義および記載されるとおりである。 It has now been found that the compounds of the present invention, and pharma- ceutically acceptable compositions thereof, are effective as degraders of CDK2 or CDK2 and CCNE1 proteins. Such compounds have the general formula I:

or a pharma- ceutically acceptable salt thereof, where each variable is as defined and described herein.

The compounds of the present invention, and pharma- ceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of the CDK2 protein, including those described herein.

The compounds provided by the present invention are also useful for the study of CDK2 protein in biological and pathological phenomena; and for the comparative evaluation of novel CDK2 inhibitors or CDK2 degraders in vitro or in vivo.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS 1. General description of specific embodiments of the present invention:
The compounds of the present invention, and compositions thereof, are useful as degraders and/or inhibitors of CDK proteins. In some embodiments, provided compounds degrade and/or inhibit CDK2 proteins. In some embodiments, provided compounds degrade CDK2 and CCNE1 proteins.

の化合物またはその薬学的に受容可能な塩を提供し、式Ｉにおいて：
ＣＢＭは、ＣＤＫ２またはＣＤＫ２およびＣＣＮＥ１を結合することが可能なＣＤＫ結合部分であり；
Ｌは、ＣＢＭをＤＩＭに結合させる二価部分であり；そして
ＤＩＭは、分解誘導部分、例えば、リガーゼ結合部分（ＬＢＭ）、リジン模倣物、または水素原子である。 In certain embodiments, the present invention provides a compound of formula I:

or a pharma- ceutically acceptable salt thereof, in formula I:
CBM is a CDK-binding moiety capable of binding CDK2 or CDK2 and CCNE1;
L is a bivalent moiety that links the CBM to the DIM; and DIM is a cleavage-inducing moiety, e.g., a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.

2. Compounds and Definitions:
The compounds of the present invention include those generally described above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, Eds.: Smith, M. B. and March, J. M., the entire contents of which are incorporated herein by reference. , John Wiley & Sons, New York: 2001.

The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic, bicyclic, bridged bicyclic, or spirocyclic hydrocarbon (also referred to herein as "carbocyclic,""alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic _C3 - _C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, saturated or unsaturated, alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

が挙げられる。 As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) having at least one bridge, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is attached to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include:

Examples include:

The term "lower alkyl" refers to a _C1-4 straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to a _C1-4 straight or branched chain alkyl group substituted with one or more halogen atoms.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR ⁺ (as in N-substituted pyrrolidinyl)).

The term "unsaturated" as used herein means a moiety having one or more units of unsaturation.

As used herein, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent straight or branched alkylene chains, alkenylene chains, and alkynylene chains, as defined herein.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH ₂ ) _n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group that contains at least one double bond and in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

の二価のシクロプロピル基をいう。 As used herein, the term "cyclopropylenyl" refers to the following structure:

The divalent cyclopropyl group is

The term "halogen" means F, Cl, Br, or I.

The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl rings may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺ NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring may be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. Heterocyclyl rings can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable portion of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be either the same or different at each position. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable compounds, or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH ₂ ) _{0-4 R o ; -(CH 2 ) 0-4 OR o} ^; -O(CH ₂ ) _0-4 R ^o _{, -O-(CH 2 ) 0-4 C(O)OR o ; -(CH 2} ⁾ _0-4 ^CH _{( OR} ^o ) ₂ ; -(CH ₂ ) _0-4 SR ^o ; -(CH ₂ ) _0-4 Ph (which may be substituted by R ^o ); -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph (which may be substituted by R ^o ); -CH=CHPh (which may be substituted by R ^o ); -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl (which may be substituted by R ^o ); -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _{0 to 4} N(R ^○ ) ₂ ; -(CH ₂ ) _{0 to 4} N(R ^○ )C(O)R ^○ ; -N(R ^○ )C(S)R ^○ ; -(CH ₂ ) _{0 to 4} N(R ^○ )C(O)NR ^○ ₂ ; -N(R ^○ )C(S)NR ^○ ₂ ; -(CH ₂ ) _{0 to 4} N(R ^○ )C(O)OR ^○ ; -N(R ^○ )N(R ^○ )C(O)R ^○ ; -N(R ^○ )N(R ^○ )C(O)NR ^○ ₂ ; -N(R ^○ )N(R ^○ )C(O)OR ^○ ; -(CH ₂ ) _{0 to 4} C(O)R ^○ ; -C(S)R ^○ ; -(CH _２ ） _0～4 C(O)OR ^○ ；－（ _CH２ ） _0～4 C(O)SR ^○ ；－（ _CH２ ） _0～4 C(O)OSiR ^○ _３ ；－（ _CH２ ） _0～4 OC(O)R ^○ ；－OC(O)( _CH２ ） _0～4 SR- ；－（ _CH２ ） _0～4 SC(O)R ^○ ；－（ _CH２ ） _0～4 C(O)NR ^○ _２ ；－C(S)NR ^○ _２ ；－C(S)SR ^○ ；－SC(S)SR ^○ 、－（ _CH２ ） _0～4 OC(O)NR ^○ ₂ ；－C(O)N(OR ^○ )R ^○ ；－C(O)C(O)R ^○ ；－C(O) _CH２C (O)R ^○ ;-C(NOR ^○ )R ^○ ;-(CH ₂ ) _0-4 SSR ^○ ;-(CH ₂ ) _0-4 S(O) ₂ R ^○ ;-(CH ₂ ) _0-4 S(O) ₂ OR ^○ ;-(CH ₂ ) _{0-4 OS(O) 2} R ^○ ;-S(O) ₂ NR ^○ ₂ ;-(CH ₂ ) _0-4 S(O)R ^○ ;-N(R ^○ )S(O) ₂ NR ^○ ₂ ;-N(R ^○ )S(O) ₂ R ^○ ;-N(OR _○ )R ^○ ;-C(NH ₎ NR ^○ ₂ ;-P(O) ₂ R ^○ ;-P(O)R ^{○ 2} ;-OP(O)R ^○ ₂ ;-OP(O)(OR ^○ ) ₂ SiR ^o ₃ ; -(C _1-4 straight or branched alkylene)O-N(R ^o ) ₂ ; or -(C _1-4 straight or branched alkylene)C(O)O-N(R ^o ) ₂ , where each R ^o may be substituted as defined below and is independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ - (5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, R Two independent occurrences of ^◯ , together with the atom(s) between them, form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

Suitable monovalent substituents on R ^○ (a ring formed by two independent occurrences of R ^○ together with the atom between them) are independently halogen, -(CH ₂ ) _0-2 R ^● , -(haloR ^● ), -(CH 2 ) 0-2 OH, _- (CH ₂ ) _0-2 OR ^● , -(CH ₂ ) _0-2 CH(OR ^● ) ₂ ; -O(haloR ^● ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^● , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^● , -(CH _{2 ) 0-2} SR ^● , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^● , -( _CH2 ) _0-2NR ^● ₂ , _-NO2 , -SiR ^● ₃ , -OSiR ^● ₃ , -C(O)SR ^● , -( _C1-4 straight or branched alkylene)C(O)OR ^● , or -SSR ^● , where each R ^● is unsubstituted or, if preceded by "halo", substituted with only one or more halogens, and is independently selected from _C1-4 aliphatic, _-CH2Ph , -O( _CH2 ) _0-1Ph , or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^○ include =O and =S.

Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) _2R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3O- , or -S(C(R ^* ₂ )) _2-3S- , where each independent occurrence of R ^* is selected from hydrogen, a _C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR ^* ₂ ) _2-3O- , where each independent occurrence of R ^* is selected from hydrogen, a _C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogen, -R ^● , -(haloR ^● ), -OH, -OR ^● , -O(haloR ^● ), -CN, -C(O)OH, -C(O)OR ^● , _-NH2 , -NHR ^● , -NR ^● ₂ , or _-NO2 , where each R ^● is unsubstituted or, when preceded by "halo", substituted with only one or more halogens, and independently is a _C1-4 aliphatic, _-CH2Ph , -O( _CH2 ) _0-1Ph , or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ^† , -NR ^† ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C(O)R ^† , -C(O) _CH2C (O)R ^† , -S(O) _2R ^† , -S(O) _2NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH)NR ^† ₂ , or -N(R ^† )S(O) _2R ^† ; where each R ^† is independently hydrogen, a _C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, R Two independent occurrences of ^† taken together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on an aliphatic group of R ^† are independently halogen, -R ^● , -(haloR ^● ), -OH, -OR ^● , -O(haloR ^● ), -CN, -C(O)OH, -C(O)OR ^● , _-NH2 , -NHR ^● , -NR ^● ₂ , or _-NO2 , where each R ^● is unsubstituted or, when preceded by "halo", substituted with only one or more halogens, and independently a _C1-4 aliphatic, _-CH2Ph , -O( _CH2 ) _0-1Ph , or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As used herein, the term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids), or by using other methods used in the art, such as ion exchange. Other pharma-ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. These include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, where appropriate, formed using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. In some embodiments, provided compounds are purified in salt form for convenience and/or ease of purification, e.g., using acidic or basic mobile phases during chromatography. Salt forms of provided compounds formed during chromatographic purification are contemplated herein and will be readily apparent to one of skill in the art.

Unless otherwise stated, a structure depicted herein is also meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, a structure depicted herein is also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by ^{a 13} C or ¹⁴ C enriched carbon, are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

As used herein, the term "provided compounds" refers to any genus, subgenus, and/or species described herein.

As used herein, the term "inhibitor" is defined as a compound that binds and/or inhibits CDK2 or CDK2 and CCNE1 with measurable affinity. In certain embodiments, inhibitors have an IC50 and/or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about ₁₀₀ nM, less than about 10 nM, or less than about 1 nM.

As used herein, the term "degrader" is defined as a heterobifunctional compound that binds with measurable affinity to and/or inhibits both CDK2 or CDK2 and CCNE1 and an E3 ligase, resulting in ubiquitination and subsequent degradation of CDK2 or CDK2 and CCNE1. In certain embodiments, degraders have a DC 50 of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. As used herein, the term "monovalent _" refers to a degrader compound that does not have an E3 ligase binding moiety attached.

The compounds of the present invention may be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that may be covalently attached to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol or hydroxyl moieties, to name a few. It is understood that such moieties may be attached directly to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached by click chemistry. In some embodiments, such moieties may be attached by 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and are described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41:2596-9 and Sun et al., Bioconjugate Chem., 2006, 17:52-7.

As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, ³² P, ³³ P, ³⁵ S, or ¹⁴ C), mass tags, and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate for the generation of a detectable signal. For biotin, secondary intermediates may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradioactive fluorescence resonance energy transfer (FRET), and the second group produces the signal that is detected.

As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY 680, and Alexa Fluor 680), and the like. TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), cascade blue, cascade yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride, These include, but are not limited to, oxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophore release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconate, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Pat. Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 Daltons) may be used as mass tags.

The terms "measurable affinity" and "measurably inhibit" as used herein refer to a measurable change in CDK2 or CDK2 and CCNE1 activity between a sample containing a compound of the invention or a composition thereof and CDK2 or CDK2 and CCNE1 and an equivalent sample containing CDK2 or CDK2 and CCNE1 in the absence of the compound or composition thereof.

の化合物またはその薬学的に受容可能な塩を提供し、式Ｉにおいて：
ＣＢＭは、ＣＤＫ２またはＣＤＫ２およびＣＣＮＥ１を結合することが可能なＣＤＫ結合部分であり；
Ｌは、ＣＢＭをＤＩＭに結合させる二価部分であり；そして
ＤＩＭは、分解誘導部分、例えば、リガーゼ結合部分（ＬＢＭ）、リジン模倣物、または水素原子である。 3. Description of the Exemplary Embodiments:
As noted above, in certain embodiments, the present invention provides a compound of formula I:

or a pharma- ceutically acceptable salt thereof, in formula I:
CBM is a CDK-binding moiety capable of binding CDK2 or CDK2 and CCNE1;
L is a bivalent moiety that links the CBM to the DIM; and DIM is a cleavage-inducing moiety, e.g., a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.

CDK2 binding moiety (CBM)
As defined herein and described above, a CBM is a CDK-binding moiety capable of binding a CDK2 protein. In some embodiments, a CBM binds to a CDK2 protein, which then undergoes ubiquitination, thereby marking CDK2 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, a CBM is a CDK-binding moiety capable of binding and degrading CDK2 selectively over other CDK proteins (e.g., CDK1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, etc.). In some embodiments, a CBM is a CDK-binding moiety capable of binding and degrading CDK2 selectively over one or more of CDK1, CDK4, and CDK9 proteins.

In some embodiments, CBM binds to CDK2 and CCNE1 proteins, which then undergo ubiquitination, thereby marking CDK2 and CCNE1 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, the compounds provided are dual degraders of CDK2 and CCNE1.

As defined herein and described below, formulas may be expressed using square brackets, e.g.,
When depicted as: L is attached to a modifiable carbon, oxygen, or nitrogen atom in the CBM, including substitution or replacement of defined groups in the CBM.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして：
Ｒ^ａおよびＲ^ｂは独立して、水素もしくはＲ^Ａであるか、あるいは
Ｒ^ａおよびＲ^ｂは、これらが結合している窒素と一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^Ａは独立して、Ｃ_１～６脂肪族、フェニル、３員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｗ、環Ｘ、および環Ｙは独立して、フェニル、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される環であり；
環Ｚは、フェニル、または４員～８員の飽和もしくは部分不飽和の、単環式、二環式、有橋二環式、もしくはスピロ環式の、カルボシクリル、もしくは窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリルであり；
Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、およびＲ^ｚは独立して、水素、Ｒ^Ａ、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）ＮＲＯＲ、－ＣＲ_２ＮＲＣ（Ｏ）Ｒ、－ＣＲ_２ＮＲＣ（Ｏ）ＮＲ_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）Ｎ（Ｒ）_２、－ＮＲＳ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－ＮＲＰ（Ｏ）（ＯＲ）_２、－ＮＲＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＮＲＰ（Ｏ）（ＮＲ_２）_２、および－ＮＲＳ（Ｏ）_２Ｒから選択され；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、４員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
Ｌ^ｘは、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の、飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－ＣＦ_２－、－ＣＲＦ－、－ＮＲ－、－Ｓ－、－Ｓ（Ｏ）－、－Ｓ（Ｏ）_２－または－ＣＲ＝ＣＲ－で必要に応じて置き換えられており；
ｖは、０または１であり；そして
ｗ、ｘ、ｙ、およびｚは独立して、０、１、２、３、または４である。 In certain embodiments, the present invention provides a compound according to the invention, wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, thereby having formula I-a:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and
R ^a and R ^b are independently hydrogen or R ^A , or R ^a and R ^b together with the nitrogen to which they are attached form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring W, Ring X, and Ring Y are independently rings selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . selected from -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ^x is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして：
環Ｗおよび環Ｘは独立して、ベンゾ、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される縮合環であり；
環Ｙは、フェニル、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される環であり；
環Ｚは、フェニル、または４員～８員の飽和もしくは部分不飽和の、単環式、二環式、有橋二環式、もしくはスピロ環式の、カルボシクリル、もしくは窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリルであり；
Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、およびＲ^ｚは独立して、水素、Ｒ^Ａ、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）ＮＲＯＲ、－ＣＲ_２ＮＲＣ（Ｏ）Ｒ、－ＣＲ_２ＮＲＣ（Ｏ）ＮＲ_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）Ｎ（Ｒ）_２、－ＮＲＳ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－ＮＲＰ（Ｏ）（ＯＲ）_２、－ＮＲＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＮＲＰ（Ｏ）（ＮＲ_２）_２、および－ＮＲＳ（Ｏ）_２Ｒから選択されるか；あるいは
同じ炭素原子に結合している２個のＲ^ｗ基は、必要に応じて一緒になって、３員～５員の飽和または部分不飽和のカルボシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する３員～５員の飽和または部分不飽和のヘテロシクリルから選択されるスピロ縮合環を形成し；
各Ｒ^Ａは独立して、Ｃ_１～６脂肪族、フェニル、３員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、４員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；そして
Ｌ^ｘは、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の、飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－ＣＦ_２－、－ＣＲＦ－、－ＮＲ－、－Ｓ－、－Ｓ（Ｏ）－、－Ｓ（Ｏ）_２－または－ＣＲ＝ＣＲ－で必要に応じて置き換えられており；
ｖは、０または１であり；そして
ｗ、ｘ、ｙ、およびｚは独立して、０、１、２、３、または４である。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, whereby the compound has formula I-b:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and
Ring W and Ring X are independently a fused ring selected from benzo, 4- to 7-membered saturated or partially unsaturated, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Y is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R; or two R ^w groups attached to the same carbon atom optionally join together to form a spiro-fused ring selected from 3- to 5-membered saturated or partially unsaturated carbocyclyl, and 3- to 5-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen optionally taken together with the atoms between them form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L ^x is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain in which one to two methylene units of the chain are optionally replaced independently with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして：
環Ｗ、環Ｘ、および環Ｙは独立して、フェニル、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される環であり；
環Ｚは、フェニル、または４員～８員の飽和もしくは部分不飽和の、単環式、二環式、有橋二環式、もしくはスピロ環式の、カルボシクリル、もしくは窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリルであり；
Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、およびＲ^ｚは独立して、水素、Ｒ^Ａ、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）ＮＲＯＲ、－ＣＲ_２ＮＲＣ（Ｏ）Ｒ、－ＣＲ_２ＮＲＣ（Ｏ）ＮＲ_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）Ｎ（Ｒ）_２、－ＮＲＳ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－ＮＲＰ（Ｏ）（ＯＲ）_２、－ＮＲＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＮＲＰ（Ｏ）（ＮＲ_２）_２、および－ＮＲＳ（Ｏ）_２Ｒから選択され；
各Ｒ^Ａは独立して、Ｃ_１～６脂肪族、フェニル、３員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
Ｌ^ｘは、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の、飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－ＣＦ_２－、－ＣＲＦ－、－ＮＲ－、－Ｓ－、－Ｓ（Ｏ）－、－Ｓ（Ｏ）_２－または－ＣＲ＝ＣＲ－で必要に応じて置き換えられており；
ｖは、０または１であり；そして
ｗ、ｘ、ｙ、およびｚは独立して、０、１、２、３、または４である。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, thereby having formula I-c:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and
Ring W, Ring X, and Ring Y are independently rings selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . selected from -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ^x is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして：
Ｒ^ａおよびＲ^ｂは独立して、水素もしくはＲ^Ａであるか、あるいは
Ｒ^ａおよびＲ^ｂは、これらが結合している窒素と一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^Ａは独立して、Ｃ_１～６脂肪族、フェニル、３員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｗは、フェニル、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される環であり；
環Ｘは、ナフチル、９員～１０員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する９員～１０員のヘテロアリールから選択される二環式環であり；
環Ｚは、フェニル、または４員～８員の飽和もしくは部分不飽和の、単環式、二環式、有橋二環式、もしくはスピロ環式の、カルボシクリル、もしくは窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリルであり；
Ｒ^ｗ、Ｒ^ｘ、およびＲ^ｚは独立して、水素、Ｒ^Ａ、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）ＮＲＯＲ、－ＣＲ_２ＮＲＣ（Ｏ）Ｒ、－ＣＲ_２ＮＲＣ（Ｏ）ＮＲ_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）Ｎ（Ｒ）_２、－ＮＲＳ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－ＮＲＰ（Ｏ）（ＯＲ）_２、－ＮＲＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＮＲＰ（Ｏ）（ＮＲ_２）_２、および－ＮＲＳ（Ｏ）_２Ｒから選択され；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、４員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
Ｌ^ｘは、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の、飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－ＣＦ_２－、－ＣＲＦ－、－ＮＲ－、－Ｓ－、－Ｓ（Ｏ）－、－Ｓ（Ｏ）_２－または－ＣＲ＝ＣＲ－で必要に応じて置き換えられており；
ｖは、０または１であり；そして
ｗ、ｘ、およびｚは独立して、０、１、２、３、または４である。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, whereby the compound has formula I-d:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and
R ^a and R ^b are independently hydrogen or R ^A , or R ^a and R ^b together with the nitrogen to which they are attached form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring W is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring X is a bicyclic ring selected from naphthyl, a 9- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NROR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) _{2 .} selected from -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ^x is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1; and w, x, and z are independently 0, 1, 2, 3, or 4.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして：
環Ｗおよび環Ｘは独立して、フェニル、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される環であり；
環Ｙは、フェニル、４員～７員の飽和または部分不飽和の、カルボシクリル、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリールから選択される環であり；
環Ｚは、フェニル、または４員～８員の飽和もしくは部分不飽和の、単環式、二環式、有橋二環式、もしくはスピロ環式の、カルボシクリル、もしくは窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリルであり；
Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、およびＲ^ｚは独立して、水素、Ｒ^Ａ、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）ＮＲＯＲ、－ＣＲ_２ＮＲＣ（Ｏ）Ｒ、－ＣＲ_２ＮＲＣ（Ｏ）ＮＲ_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）Ｎ（Ｒ）_２、－ＮＲＳ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－ＮＲＰ（Ｏ）（ＯＲ）_２、－ＮＲＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＮＲＰ（Ｏ）（ＮＲ_２）_２、および－ＮＲＳ（Ｏ）_２Ｒから選択されるか；あるいは
同じ炭素原子に結合している２個のＲ^ｗ基は、必要に応じて一緒になって、３員～５員の飽和または部分不飽和のカルボシクリル、ならびに窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する３員～５員の飽和または部分不飽和のヘテロシクリルから選択されるスピロ縮合環を形成し；
各Ｒ^Ａは独立して、Ｃ_１～６脂肪族、フェニル、３員～７員の飽和または部分不飽和の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、これらが結合している窒素原子に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；そして
Ｌ^ｘおよびＬ^ｙは独立して、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の、飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－ＣＦ_２－、－ＣＲＦ－、－ＮＲ－、－Ｓ－、－Ｓ（Ｏ）－、－Ｓ（Ｏ）_２－または－ＣＲ＝ＣＲ－で必要に応じて置き換えられており；
ｖは、０または１であり；そして
ｗ、ｘ、ｙ、およびｚは独立して、０、１、２、３、または４である。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, whereby the compound has formula I-e:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and
Ring W and Ring X are independently a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Y is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R; or two R ^w groups attached to the same carbon atom optionally join together to form a spiro-fused ring selected from 3- to 5-membered saturated or partially unsaturated carbocyclyl, and 3- to 5-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen optionally taken together with the atoms between them form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L ^x and L ^y are independently a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain in which one to two methylene units of the chain are optionally replaced independently with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1; and w, x, y, and z are independently 0, 1, 2, 3, or 4.

As generally defined above, R ^a and R ^b are independently hydrogen or R ^A , or R ^a and R ^b together with the nitrogen to which they are attached form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^a is hydrogen. In some embodiments, R ^a is R ^A. In some embodiments, R ^b is hydrogen. In some embodiments, R ^b is R ^A. In some embodiments, R ^a and R ^b together with the nitrogen to which they are attached form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^a is isopropyl. In some embodiments, R ^a and R ^b taken together represent:
Form.

In some embodiments, R ^a and R ^b are selected from those depicted in Table 1 below.

As generally defined above, each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^A is an optionally substituted C _1-6 aliphatic. In some embodiments, R is a C _1-6 alkyl (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is a C _1-6 haloalkyl (e.g., -CF ₃ , CHF ₂ , etc.). In some embodiments, R ^A is an optionally substituted phenyl. In some embodiments, R ^A is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R ^A is an optionally substituted heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ^A is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each R ^A is selected from those depicted in Table 1 below.

As generally defined above, rings W, X, and Y are independently rings selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, one or more of rings W, X, and Y are rings selected from phenyl. In some embodiments, one or more of rings W, X, and Y are 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more of rings W, X, and Y are 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As generally defined above, rings W and X are independently fused rings selected from benzo, 4- to 7-membered saturated or partially unsaturated carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, one or more of rings W and X are benzo. In some embodiments, one or more of rings W and X are fused 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more of rings W and X are fused 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As generally defined above, ring X is a bicyclic ring selected from naphthyl, 9- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ring X is naphthyl. In some embodiments, ring X is a 9- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring X is a 9- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ring W is cyclopentyl. In some embodiments, ring W is cyclohexyl. In some embodiments, ring W is
In some embodiments, ring W is
In some embodiments, ring W is
In some embodiments, ring W is
It is.

In some embodiments, ring W is
In some embodiments, ring W is
In some embodiments, ring W is
In some embodiments, ring W is
In some embodiments, ring W is
It is.

In some embodiments, ring X is
In some embodiments, ring X is
In some embodiments, ring X is
It is.

In some embodiments, ring X is
In some embodiments, ring X is
In some embodiments, ring X is
In some embodiments, ring X is
It is.

In some embodiments, ring W, ring X, and ring Y are selected from those depicted in Table 1 below.

As generally defined above, ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ring Z is phenyl. In some embodiments, ring Z is a 4-8 membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl. In some embodiments, ring Z is a 4-8 membered, saturated or partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ring Z is cyclohexane.

In some embodiments, ring Z is selected from those depicted in Table 1 below.

As generally defined above, R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NROR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) _{2 .} or two R w groups _attached to _{the same carbon} atom _{are optionally joined together} to form a spiro ^-fused ring selected from a _3- to ₅ -membered saturated or partially unsaturated carbocyclyl and a _3- to 5-membered saturated or partially unsaturated heterocyclyl having 1 to ₂ heteroatoms independently selected from nitrogen, _oxygen , and sulfur.

In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are hydrogen. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are R ^A. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are halogen. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -CN. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NO _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OR. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -SR. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NR _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R z are -SiR _3. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -S(O) ₂ R. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -S(O) ₂ NR _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -S(O)R. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -C(O) ^R . In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -C(O)OR. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -C(O)NR _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^{z are -C(O)NROR. In some embodiments, one or more of R w , R x , R y , and R z are -CR 2 NRC} ₍ O)R. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -CR ₂ NRC(O)NR ₂ . In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OC(O)R. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OC(O)NR _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OP(O)R _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OP(O)(OR) _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OP(O)(OR)NR ₂ . In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -OP(O)(NR ₂ ) ₂ -. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRC(O)OR. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRC(O)R. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRC(O)N(R) _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRS(O) ₂ R. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NP(O)R _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRP(O)(OR) _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRP(O)(OR)NR _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRP(O)(NR ₂ ) _2. In some embodiments, one or more of R ^w , R ^x , R ^y , and R ^z are -NRS(O) ₂ R. In some embodiments, two R ^w groups attached to the same carbon atom are joined together to form a 3- to 5-membered saturated or partially unsaturated carbocyclic spiro-fused ring. In some embodiments, two R ^w groups attached to the same carbon atom are optionally joined together to form a 3- to 5-membered saturated or partially unsaturated heterocyclic spiro-fused ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

である。いくつかの実施形態において、Ｒ^ｗは

である。いくつかの実施形態において、Ｒ^ｗは
である。いくつかの実施形態において、２個のＲ^ｗは環化して、シクロプロピレニルを形成する。 In some embodiments, R ^w is fluoro. In some embodiments, R ^w is chloro. In some embodiments, R ^w is bromo. In some embodiments, R ^w is methyl. In some embodiments, R ^w is isopropyl. In some embodiments, R w is _-CHF2 . In some embodiments, R ^{w is -CF3. In some embodiments, R w} _is ^-CH2CHF2 _. In some embodiments, R ^w is _-CH2CF3 . In some embodiments, R ^w is _{-CH(Me)CF3. In some embodiments, R w is -CONH2 . In} ^some _embodiments , R ^{w is}

In some embodiments, ^Rw is

In some embodiments, ^Rw is
In some embodiments, two ^Rw cyclize to form cyclopropylenyl.

In some embodiments, R ^x is bromo. In some embodiments, R ^x is _-CF3 . In some embodiments, R ^x is -O-Ci _-6cycloalkyl . In some embodiments, R ^x is -O-cyclohexyl.

In some embodiments, R ^y is methyl.

In some embodiments, R ^w , R ^x , R ^y , and R ^z are selected from those depicted in Table 1 below.

As generally defined above, each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally combine with atoms between them to form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C _{1-6 aliphatic. In some embodiments, R is a C 1-6 alkyl} (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is a C _1-6 haloalkyl (e.g., -CF ₃ , CHF ₂ , etc.). In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

As generally defined above, L ^x and L ^y are independently a covalent bond or a C _1-3 divalent linear or branched, saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-.

In some embodiments, L ^x is a covalent bond. In some embodiments, L ^x is a C _1-3 divalent linear or branched, saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-.

In some embodiments, L ^y is a covalent bond. In some embodiments, L ^y is a C _1-3 divalent linear or branched, saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-.

In some embodiments, L ^x is -C(O)- In some embodiments, L ^x is -S(O) ₂ -.

In some embodiments, L ^y is —C(O)—.

In some embodiments, ^Lx and ^Ly are selected from those depicted in Table 1 below.

As generally defined above, v is 0 or 1.

In some embodiments, v is 0. In some embodiments, v is 1.

In some embodiments, v is selected from those depicted in Table 1 below.

As generally defined above, w, x, y, and z are independently 0, 1, 2, 3, or 4.

In some embodiments, one or more of w, x, y, and z are 0. In some embodiments, one or more of w, x, y, and z are 1. In some embodiments, one or more of w, x, y, and z are 2. In some embodiments, one or more of w, x, y, and z are 3. In some embodiments, one or more of w, x, y, and z are 4.

In some embodiments, w, x, y, and z are selected from those depicted in Table 1 below.

In some embodiments, the CBM comprises:
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
In some embodiments, the CBM is
It is.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、およびＲ^３の各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／１５７６５２およびＵＳ ２０２０／２４７７８４で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-1:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , and ^R3 are as defined and described in WO 2020/157652 and US 2020/247784, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、環Ａ、およびｎの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／１６８１９７およびＵＳ ２０２０／３９２１３９で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-2:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , ^R5 , ring A, and n are as defined and described in WO 2020/168197 and US 2020/392139, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｘ、およびＹの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／２０５５６０およびＵＳ ２０２０／３９９２７３で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-3:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , ^R5 , ^R6 , ^R7 , ^R8 , X, and Y are as defined and described in WO 2020/205560 and US 2020/399273, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^２Ａ、Ｒ^２Ｂ、Ｒ^３、Ｒ^４、ｐ、ｑ、およびｒの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０１８／０３３８１５およびＵＳ １０，２３３，１８８で定義および記載されるとおりである。 In certain embodiments, the present invention relates to a compound wherein the CBM is a CDK2/4/6 binding moiety, whereby the compound has formula I-e-4:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R2A , ^R2B , ^R3 , ^R4 , p, q, and r are as defined and described in WO 2018/033815 and US 10,233,188, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４および環Ａの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／２０６１３７で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-5:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , ^R4 and ring A are as defined and described in WO 2020/206137, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、ｎおよび環Ａの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／１８０９５９およびＵＳ ２０２１／０１７１５６で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-6:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , n, and ring A are as defined and described in WO 2020/180959 and US 2021/017156, each of which is incorporated by reference in its entirety herein.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、およびＲ^７の各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／１６８１７８およびＵＳ ２０２０／３１６０６４で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-7:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , and ^R7 are as defined and described in WO 2020/168178 and US 2020/316064, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^３、Ｒ^８、Ｒ^８’、Ｒ^Ａ、Ｘ^１、Ｙ、Ｚ^１、Ｚ^２、ｎ、ｍ、および環Ａの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／２２３５５８およびＵＳ ２０２０／３４７０６６で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-8:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R3 , ^R8 , R8 ^' , R, ^X1 , Y, ^Z1 , ^Z2 , n, m, and ring ^A are as defined and described in WO 2020/223558 and US 2020/347066, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^３、Ｒ^８、Ｘ^１、Ｘ^２、Ｘ^３、Ｙ、Ｚ^１、Ｚ^２、ｎ、および環Ａの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２０／２２３４６９およびＵＳ ２０２０／３４７０６７で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-9:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R3 , ^R8 , ^X1 , ^X2 , ^X3 , Y, ^Z1 , ^Z2 , n, and ring A are as defined and described in WO 2020/223469 and US 2020/347067, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＤＩＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、環Ａ、環Ｂ、Ｘ、Ｙ、Ｚ、ｎ、およびｐの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０２１／０７２２３２で定義および記載されるとおりである。 In certain embodiments, the present invention provides compounds wherein the CBM is a CDK2 binding moiety, such as those of formula I-e-10:

or a pharma- ceutically acceptable salt thereof, wherein L and DIM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R4 , ^R5 , Ring A, Ring B, X, Y, Z, n, and p are as defined and described in WO 2021/072232, each of which is incorporated by reference in its entirety herein.

In certain embodiments, the invention provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein CBM is a CDK2 binding moiety selected from any one of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XX1, XXII, XXIII, and XXIV, wherein L and DIM are as defined above and described in embodiments herein, and the variables R1, R3, R11, R14, R16, R17, R18, R19, R20, R31, R32, R32*, Rx, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X33, X4, ^X5 , X6, X18, X19, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, ^X33 , X34, X35, X36, ^X37 , X38, ^X39 , X40, X41, X42, ^X43 , ^X44 , ^X45 , X46, ^X47 , X48, X49, X50, X51, X52, ^X53 , X54, X55, X56, ^X57 , X58, ^X59 , X60 ^{, X61} , X62, X63, X64, ^X65 , X66, X67, X68, ^X69 , ^X70 , X71, ^X72 , X73, X74, ^X75 , ^X76 , ^X77 , X78 Each of ^X , ^X , X, ^X , ^X , y and y2 is as defined and described in WO 2020/206034, each of which is incorporated by reference in its entirety.

Ligase Binding Moiety (LBM)
In some embodiments, the DIM is an LBM. In some embodiments, the LBM is a cyclic amine, as described in M. Touré, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017,13,675, WO 2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO 2012/003281, US 2013/0190340, US 2016/0022642, WO 2014/063061, US 2015/0274738, WO 2016/118666, US 2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US 2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US 2017/0008904, WO 2017/011590, US 2017/0037004, WO 2017/079267, US 2017/0121321, WO 2017/117473, WO 2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, US 2019/0076540, WO 2017/197046, US 2019/0076542, WO 2017/197051, US and E3 ligase ligands known to those of skill in the art, including those described in US 2019/0076539, WO 2017/197055, US 2019/0076541, and WO 2017/197056, each of which is incorporated by reference in its entirety.

と図示される場合、Ｌは、ＤＩＭまたはＬＢＭ中の定義される基の置換または置き換えを含めた、ＤＩＭまたはＬＢＭ内の修飾可能な炭素原子、酸素原子、または窒素原子に結合している。 As defined herein and described below, formulas may be expressed using square brackets, e.g.,

Wherein L is attached to a modifiable carbon, oxygen, or nitrogen atom in the DIM or LBM, including substitution or replacement of defined groups in the DIM or LBM.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^２は、炭素原子またはケイ素原子であり；
Ｘ^３は、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－Ｓｉ（Ｒ_２）－から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－Ｎ（Ｒ）_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）_２Ｒ、－Ｓｉ（ＯＨ）（Ｒ）_２、－Ｓｉ（Ｒ）_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）（ＮＲ_２）、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）（ＮＲ_２）、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
環Ａは、

から選択される二環式環または三環式環であり、ここで
環Ｂは、６員アリール、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
Ｒ^３は、水素、ハロゲン、－ＯＲ、－Ｎ（Ｒ）_２、または－ＳＲから選択され；
各Ｒ^４は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
Ｒ^５は、水素、Ｃ_１～４脂肪族、または－ＣＮであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、および窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；
ｍは、０、１、２、３または４であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the present invention provides a method for the treatment of cancer, wherein the LBM is a cereblon E3 ubiquitin ligase binding moiety, whereby the LBM has the formula I-aa:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom or a silicon atom;
^X3 is a divalent moiety selected from _-CR2- , -NR-, -O-, -S-, or -Si( _R2 )-;
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic;
Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) _. -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R, -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)(NR ₂ ) ₂ , or -N(R)S(O) ₂ R;
Ring A is

wherein Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R ³ is selected from hydrogen, halogen, —OR, —N(R) ₂ , or —SR;
each R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
m is 0, 1, 2, 3 or 4;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

When the point of attachment of -(R ² ) _m is depicted on ring B, it is intended, and one of ordinary skill in the art will understand, that the point of attachment of -(R ² ) _m can be on ring A, and also can be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. When -R ² is attached to a nitrogen atom that is bonded to R ⁴ or R ⁵ , then R ⁴ or R ⁵ are not present and -R ² takes the place of the R ⁴ or R ⁵ group. When -R ² is attached to a carbon atom that is bonded to R ³ , then R ³ is not present and -R ² takes the place of the R ³ group.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ａ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、Ｘ^１、Ｘ^２、Ｘ^３、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-aa above has formula I-aa′ or formula I-aa″:

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring A, L, ^L1 , ^R1 , ^R2 , ^X1 , ^X2 , ^X3 , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
環Ａは、

から選択される二環式環または三環式環であり、ここで
環Ｂは、６員アリール、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
Ｒ^３は、水素、ハロゲン、－ＯＲ、－Ｎ（Ｒ）_２、または－ＳＲから選択され；
各Ｒ^４は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
Ｒ^５は、水素、Ｃ_１～４脂肪族、または－ＣＮであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
ｍは、０、１、２、３または４であり；そして
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of a cancer cell comprising administering to said patient a therapeutically effective amount of a cancer cell, the method comprising administering to said patient a therapeutically effective amount of a cancer cell ...

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic;
each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R;
Ring A is

where Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R ³ is selected from hydrogen, halogen, —OR, —N(R) ₂ , or —SR;
each R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
m is 0, 1, 2, 3, or 4; and each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

When the point of attachment of -(R ² ) _m is depicted on ring B, it is intended, and one of ordinary skill in the art will understand, that the point of attachment of -(R ² ) _m can be on ring A, and also can be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. When -R ² is attached to a nitrogen atom that is bonded to R ⁴ or R ⁵ , then R ⁴ or R ⁵ are not present and -R ² takes the place of the R ⁴ or R ⁵ group. When -R ² is attached to a carbon atom that is bonded to R ³ , then R ³ is not present and -R ² takes the place of the R ³ group.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ａ、Ｌ、Ｒ^１、Ｒ^２、Ｘ^１、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-cc above has formula I-cc′ or formula I-cc″:

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring A, L, R ¹ , R ² , X ¹ , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^２は、炭素原子またはケイ素原子であり；
Ｘ^３は、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－Ｓｉ（Ｒ_２）－から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）_２Ｒ、－Ｓｉ（ＯＨ）（Ｒ）_２、－Ｓｉ（Ｒ）_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
環Ｃは、

から選択される単環式環または二環式環であり；
Ｒ^２およびＲ^３ａの各々は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）（ＮＲ_２）、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）（ＮＲ_２）、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
環Ｄは、６員アリール、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択され；
各Ｒ^４は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
Ｒ^５は、水素、Ｃ_１～４脂肪族、または－ＣＮであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；
ｍは、０、１、２、３または４であり；
ｎは、０、１、２、３または４であり；
ｐは、０または１であり、ここでｐが０である場合、環Ｃと環Ｄとを結合させている結合は、
に結合しており；そして
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of a cancer cell comprising administering to said patient a therapeutically effective amount of a cancer cell, the method comprising administering to said patient a therapeutically effective amount of a cancer cell ...

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom or a silicon atom;
^X3 is a divalent moiety selected from _-CR2- , -NR-, -O-, -S-, or -Si( _R2 )-;
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic;
Ring C is

is a monocyclic or bicyclic ring selected from
Each of R ² and R ^3a is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —N(R) ₂ , —Si(R) ₃ , —S(O) ₂ R, —S(O) ₂ N(R) ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) ₂ , —C(O)N(R)OR, —C(R) ₂ N(R)C(O)R, —C(R) ₂ N(R)C(O)N(R) ₂ , —OC(O)R, —OC(O)N(R) ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)(NR ₂ ), or —OP(O)(NR ₂ ). ) ₂ --, --N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)N(R) ₂ , --N(R)S(O) ₂ R, --NP(O)R ₂ , --N(R)P(O)(OR) ₂ , --N(R)P(O)(OR)(NR ₂ ), --N(R)P(O)(NR ₂ ) ₂ , or --N(R)S(O) ₂ R;
Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is
and each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｃ、環Ｄ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、Ｒ^３ａ、Ｘ^１、Ｘ^２、Ｘ^３、ｎ、ｍ、およびｐの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-dd has formula I-dd' or formula I-dd'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring C, ring D, L, ^L1 , ^R1 , ^R2 , ^R3a , ^X1 , ^X2 , ^X3 , n, m, and p are as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、または必要に応じて置換されたＣ_１～４脂肪族であり；
環Ｃは、

から選択される単環式環または二環式環であり；
Ｒ^２およびＲ^３ａの各々は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
環Ｄは、６員アリール、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択され；
各Ｒ^４は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
Ｒ^５は、水素、Ｃ_１～４脂肪族、または－ＣＮであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
ｍは、０、１、または２であり；
ｎは、０、１、２、３または４であり；
ｐは、０または１であり、ここでｐが０である場合、環Ｃと環Ｄとを結合させている結合は、
に結合しており；そして
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, the ubiquitin ligase having the formula I-ee:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic;
Ring C is

is a monocyclic or bicyclic ring selected from
each of R ² and R ^3a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R;
Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
m is 0, 1, or 2;
n is 0, 1, 2, 3 or 4;
p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is
and each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｃ、環Ｄ、Ｌ、Ｒ^１、Ｒ^２、Ｒ^３ａ、Ｘ^１、ｎ、ｍ、およびｐの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-ee has formula I-ee' or formula I-ee'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring C, ring D, L, R ¹ , R ² , R ^3a , X ¹ , n, m, and p are as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^２は、炭素原子またはケイ素原子であり；
Ｘ^３は、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－Ｓｉ（Ｒ_２）－から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）_２Ｒ、－Ｓｉ（ＯＨ）（Ｒ）_２、－Ｓｉ（Ｒ）_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
環Ｃは、

から選択される単環式環または二環式環であり；
各々またはＲ^２およびＲ^３ａは独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）（ＮＲ_２）、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）（ＮＲ_２）、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
環Ｄは、６員アリール、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択され；
各Ｒ^４は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
Ｒ^５は、水素、Ｃ_１～４脂肪族、または－ＣＮであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；
ｍは、０、１、２、３または４であり；
ｎは、０、１、２、３または４であり；
ｐは、０または１であり；そして
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the present invention provides a method for the preparation of a polypeptide comprising the LBM of formula I-ff:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom or a silicon atom;
^X3 is a divalent moiety selected from _-CR2- , -NR-, -O-, -S-, or -Si( _R2 )-;
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic;
Ring C is

is a monocyclic or bicyclic ring selected from
Each or R ² and R ^3a are independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ). ) ₂ --, --N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)N(R) ₂ , --N(R)S(O) ₂ R, --NP(O)R ₂ , --N(R)P(O)(OR) ₂ , --N(R)P(O)(OR)(NR ₂ ), --N(R)P(O)(NR ₂ ) ₂ , or --N(R)S(O) ₂ R;
Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0 or 1; and each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｃ、環Ｄ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、Ｒ^３ａ、Ｘ^１、Ｘ^２、Ｘ^３、ｍ、ｎ、およびｐの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-ff has the formula I-ff' or I-ff'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring C, ring D, L, ^L1 , ^R1 , ^R2 , ^R3a , ^X1 , ^X2 , ^X3 , m, n, and p are as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、または必要に応じて置換されたＣ_１～４脂肪族であり；
環Ｃは、

から選択される単環式環または二環式環であり；
Ｒ^２、Ｒ^３ａ、およびＲ^４の各々は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
環Ｄは、６員アリール、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択され；
Ｒ^５は、水素、Ｃ_１～４脂肪族、または－ＣＮであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
ｍは、０、１、または２であり；
ｎは、０、１、２、３、または４であり；
ｐは、０または１であり；そして
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of an I-gg antibody, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing an I-gg antibody of the formula:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic;
Ring C is

is a monocyclic or bicyclic ring selected from
each of R ² , R ^3a , and R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
m is 0, 1, or 2;
n is 0, 1, 2, 3, or 4;
p is 0 or 1; and each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｃ、環Ｄ、Ｌ、Ｒ^１、Ｒ^２、Ｒ^３ａ、Ｘ^１、ｍ、ｎ、およびｐの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-gg has the formula I-gg' or I-gg'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring C, ring D, L, R ¹ , R ² , R ^3a , X ¹ , m, n, and p are as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^２は、炭素原子、窒素原子、またはケイ素原子であり；
Ｘ^３は、共有結合、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－ＳｉＲ_２－から選択される二価部分であり；
Ｒ^１は、存在しないか、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）_２Ｒ、－Ｓｉ（ＯＨ）Ｒ_２、－ＳｉＲ_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）ＮＲ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｅ、環Ｆ、および環Ｇの各々は独立して、６員アリール、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり、ここで環Ｅ、環Ｆ、および環Ｇは独立して、１個～２個のオキソ基で必要に応じて置換されており；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；そして
ｍは、０、１、２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、または１６である。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of at least one LBM comprising administering to said ...

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom, a nitrogen atom, or a silicon atom;
^X3 is a divalent moiety selected from a covalent bond, _-CR2- , -NR-, -O-, -S-, or _-SiR2- ;
R ¹ is absent, hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ , or an optionally substituted C _1-4 aliphatic;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -NP(O) _R2 , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR) _NR2 , -N(R)P(O)( _NR2 ) ₂ , or -N(R)S(O) _2R ;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where rings E, F, and G are independently optionally substituted with 1 to 2 oxo groups;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) ₂ - or -(C)═CH-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, ₁₄ , 15, or 16.

is depicted on ring E, ring F, or ring G,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring in which ring E or ring G is fused to ring F.

When the attachment point of -(R ² ) _m is depicted on Ring E, Ring F, or Ring G, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

is depicted on ring E, ring F, or ring G,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｅ、環Ｆ、環Ｇ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、Ｘ^１、Ｘ^２、Ｘ^３、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-hh has formula I-hh' or formula I-hh'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring E, ring F, ring G, L, ^L1 , ^R1 , ^R2 , ^X1 , ^X2 , ^X3 , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）ＮＲ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｅ、環Ｆ、および環Ｇの各々は独立して、６員アリール、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり、ここで環Ｅ、環Ｆ、および環Ｇは独立して、１個～２個のオキソ基で必要に応じて置換されており；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；
ｍは、０、１、２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、または１６であり；そして
Ｒ^４、Ｒ^１０、Ｒ^１１、Ｒ^１５、Ｗ^１、Ｗ^２、およびＸは、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１９／０９９８６８で定義されるとおりである。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of at least one of the following compounds:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -NP(O) _R2 , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR) _NR2 , -N(R)P(O)( _NR2 ) ₂ , or -N(R)S(O) _2R ;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where rings E, F, and G are independently optionally substituted with 1 to 2 oxo groups;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ¹¹ , 12, 13, 14, 15, or 16; and R ⁴ , R ¹⁰ , R 11 , R ¹⁵ , W ¹ , W ² , and X are as defined in WO 2019/099868, each of which is incorporated by reference in its entirety.

is depicted on ring E, ring F, or ring G,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring in which ring E or ring G is fused to ring F.

When the attachment point of -(R ² ) _m is depicted on Ring E, Ring F, or Ring G, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

の結合点が、環Ｅ、環Ｆ、または環Ｇ上に図示されている場合、この

の結合点は、環Ｅまたは環Ｇが環Ｆに縮合している炭素原子を含めて、環Ｅ、環Ｆ、または環Ｇ上の任意の利用可能な炭素原子または窒素原子上に存在し得ることが意図され、そしてこのことを当業者は理解する。

is depicted on ring E, ring F, or ring G,

It is intended, and one of ordinary skill in the art will understand, that the point of attachment may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｅ、環Ｆ、および環Ｇの各々は独立して、０個～３個の窒素を含む６員アリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり、ここで環Ｅ、環Ｆ、および環Ｇは独立して、１個～２個のオキソ基で必要に応じて置換されており；そして
ｍは、０、１、２、３、または４である。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of a cancer cell comprising administering to said patient a therapeutically effective amount of a cancer cell, said method comprising administering to said patient a therapeutically effective amount of a cancer cell ...

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , or -N(R)S(O) ₂ R;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl containing 0-3 nitrogens, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where rings E, F, and G are independently optionally substituted with 1-2 oxo groups; and m is 0, 1, 2, 3, or 4.

is depicted on ring E, ring F, or ring G,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring in which ring E or ring G is fused to ring F.

When the attachment point of -(R ² ) _m is depicted on Ring E, Ring F, or Ring G, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、Ｌ、環Ｅ、環Ｆ、環Ｇ、Ｌ、Ｒ^１、Ｒ^２、Ｘ^１、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-ii above has formula I-ii′ or formula I-ii″:

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, L, ring E, ring F, ring G, L, R ¹ , R ² , X ¹ , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^２は、炭素原子、窒素原子、またはケイ素原子であり；
Ｘ^３は、共有結合、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－ＳｉＲ_２－から選択される二価部分であり；
Ｒ^１は、存在しないか、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）_２Ｒ、－Ｓｉ（ＯＨ）Ｒ_２、－ＳｉＲ_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）（ＮＲ_２）、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）（ＮＲ_２）、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｅは、６員アリール、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
環Ｈは、７員～９員の、飽和もしくは部分不飽和の、カルボシクリル環、もしくはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル環から選択される縮合環であり、ここで環Ｅは、１個～２個のオキソ基で必要に応じてさらに置換されており；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；
ｍは、０、１、２、３、または４である。 In certain embodiments, the present invention provides a compound according to the present invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby comprising the compound of formula I-jj:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom, a nitrogen atom, or a silicon atom;
^X3 is a divalent moiety selected from a covalent bond, _-CR2- , -NR-, -O-, -S-, or _-SiR2- ;
R ¹ is absent, hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ , or an optionally substituted C _1-4 aliphatic;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) _. -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R, -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)(NR ₂ ) ₂ , or -N(R)S(O) ₂ R;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring H is a 7- to 9-membered, saturated or partially unsaturated, fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring E is optionally further substituted with 1 to 2 oxo groups;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
m is 0, 1, 2, 3, or 4.

is depicted on ring E or ring H,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

Where the attachment point of -(R ² ) _m is depicted on Ring E and Ring H, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be on any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

is illustrated on ring E and ring H,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｅ、環Ｈ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、Ｘ^１、Ｘ^２、Ｘ^３、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-jj has formula I-jj' or formula I-jj'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring E, ring H, L, ^L1 , ^R1 , ^R2 , ^X1 , ^X2 , ^X3 , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ｅは、６員アリール、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
環Ｈは、７員～９員の、飽和もしくは部分不飽和の、カルボシクリル環、もしくはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル環から選択される環であり、ここで環Ｅは、１個～２個のオキソ基で必要に応じてさらに置換されており；そして
ｍは、０、１、２、３、または４である。 In certain embodiments, the present invention provides a method for the treatment of cancer, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby comprising administering to the patient a therapeutically effective amount of the antibody of the formula I-kk:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , or -N(R)S(O) ₂ R;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring H is a 7- to 9-membered, saturated or partially unsaturated ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring E is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

is depicted on ring E or ring H,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

Where the attachment point of -(R ² ) _m is depicted on Ring E and Ring H, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be on any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

is illustrated on ring E and ring H,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｅ、環Ｈ、Ｌ、Ｒ^１、Ｒ^２、Ｘ^１、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-kk has formula I-kk' or formula I-kk'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring E, ring H, L, R ¹ , R ² , X ¹ , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^２は、炭素原子、窒素原子、またはケイ素原子であり；
Ｘ^３は、共有結合、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－ＳｉＲ_２－から選択される二価部分であり；
Ｒ^１は、存在しないか、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）_２Ｒ、－Ｓｉ（ＯＨ）Ｒ_２、－ＳｉＲ_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）（ＮＲ_２）、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）（ＮＲ_２）、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環ＩおよびＪの各々は独立して、６員アリール、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
環Ｋは、７員～１２員の、飽和もしくは部分不飽和の、カルボシクリル環、もしくはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル環から選択される縮合環であり、ここで環Ｈは、１個～２個のオキソ基で必要に応じてさらに置換されており；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；そして
ｍは、０、１、２、３、または４である。 In certain embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of a cancer cell comprising administering to said patient a therapeutically effective amount of a cancer cell, the method comprising administering to said patient a therapeutically effective amount of a cancer cell ...

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom, a nitrogen atom, or a silicon atom;
^X3 is a divalent moiety selected from a covalent bond, _-CR2- , -NR-, -O-, -S-, or _-SiR2- ;
R ¹ is absent, hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ , or an optionally substituted C _1-4 aliphatic;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) _. -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R, -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)(NR ₂ ) ₂ , or -N(R)S(O) ₂ R;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring K is a 7- to 12-membered, saturated or partially unsaturated, fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring H is optionally further substituted with 1 to 2 oxo groups;
^L1 is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -C(F) _2- , -N(R)-, -S-, -S(O) _2- , or -(C)=CH-; and m is 0, 1, 2, 3, or 4.

is depicted on ring I, ring J, and ring K,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

Where the attachment point of -(R ² ) _m is depicted on ring I, ring J, and ring K, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atoms to which ring I, ring J, and ring K are fused.

are illustrated on ring I, ring J, and ring K,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｉ、環Ｊ、環Ｋ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、Ｘ^１、Ｘ^２、Ｘ^３、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-ll above has formula I-ll' or formula I-ll'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring I, ring J, ring K, L, ^L1 , ^R1 , ^R2 , ^X1 , ^X2 , ^X3 , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして：
Ｘ^１は、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、または必要に応じて置換されたＣ_１～４脂肪族であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^２は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－Ｎ（Ｒ）_２、－Ｓｉ（Ｒ）_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２Ｎ（Ｒ）_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）Ｎ（Ｒ）_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環ＩおよびＪの各々は独立して、６員アリール、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を含む６員ヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
環Ｋは、７員～１２員の、飽和もしくは部分不飽和の、カルボシクリル環、もしくはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有するヘテロシクリル環から選択される縮合環であり、ここで環Ｈは、１個～２個のオキソ基で必要に応じてさらに置換されており；そして
ｍは、０、１、２、３、または４である。 In certain embodiments, the present invention provides a compound of formula I-mm:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and
X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , or -N(R)S(O) ₂ R;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring K is a 7- to 12-membered, saturated or partially unsaturated, fused ring selected from a carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring H is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

are illustrated on ring I, ring J, and ring K,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

Where the attachment point of -(R ² ) _m is depicted on ring I, ring J, and ring K, it is intended, and one of ordinary skill in the art will understand, that the attachment point of -(R ² ) _m can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atoms to which ring I, ring J, and ring K are fused.

are illustrated on ring I, ring J, and ring K,
It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

の化合物またはその薬学的に受容可能な塩として提供され、ここで：
ＣＢＭ、環Ｉ、環Ｊ、環Ｋ、Ｌ、Ｒ^１、Ｒ^２、Ｘ^１、およびｍの各々は、上で定義されたとおりである。 In some embodiments, the compound of formula I-mm has the formula I-mm' or I-mm'':

or a pharma- ceutically acceptable salt thereof, wherein:
Each of CBM, ring I, ring J, ring K, L, R ¹ , R ² , X ¹ , and m is as defined above.

の化合物またはその薬学的に受容可能な塩を提供し、ここで：
環Ｍは、

から選択され；
Ｘ^１、Ｘ^６、およびＸ^７の各々は独立して、共有結合、－ＣＨ_２－、－ＣＨＣＦ_３－、－ＳＯ_２－、－Ｓ（Ｏ）－、－Ｐ（Ｏ）Ｒ－、－Ｐ（Ｏ）ＯＲ－、－Ｐ（Ｏ）ＮＲ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^３およびＸ^５の各々は独立して、共有結合、－ＣＲ_２－、－ＮＲ－、－Ｏ－、－Ｓ－、または－ＳｉＲ_２－から選択される二価部分であり；
Ｘ^４は、

から選択される三価部分であり；
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
各Ｒ^３ａは独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－ＳｉＲ_３、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｃ（Ｒ）_２Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）Ｎ（Ｒ）_２、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２－、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＮＰ（Ｏ）Ｒ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＯＲ）ＮＲ_２、－Ｎ（Ｒ）Ｐ（Ｏ）（ＮＲ_２）_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
各Ｒ^７は独立して、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、－Ｐ（Ｏ）（ＯＲ）_２、－Ｐ（Ｏ）（ＮＲ_２）ＯＲ、－Ｐ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＨ）Ｒ_２、－Ｓｉ（ＯＨ）_２Ｒ、－ＳｉＲ_３、または必要に応じて置換されたＣ_１～４脂肪族であるか；あるいは
Ｒ^７と、Ｘ^１またはＸ^３とは、これらの間にある原子と一緒になって、５員～７員の飽和、部分不飽和の、炭素環式環、もしくはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する複素環式環を形成し；
同じ炭素上の２個のＲ^７基は、これらの間にある原子と必要に応じて一緒になって、３員～６員のスピロ縮合環、またはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の複素環式環を形成し；
隣接する炭素上の２個のＲ^７基は、これらの間にある原子と必要に応じて一緒になって、３員～７員の飽和、部分不飽和の、炭素環式環、もしくはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する複素環式環、またはホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する７員～１３員の飽和、部分不飽和の、有橋複素環式環、もしくはスピロ複素環式環を形成し；
環Ｄは、６員～１０員の、アリール、もしくは窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を含むヘテロアリール、５員～７員の飽和もしくは部分不飽和のカルボシクリル、ホウ素、窒素、酸素、ケイ素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員～７員の飽和もしくは部分不飽和のヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員ヘテロアリールから選択され；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－Ｃ（Ｒ）_２－、－ＣＨ（Ｒ）－、－Ｃ（Ｆ）_２－、－Ｎ（Ｒ）－、－Ｓ－、－Ｓ（Ｏ）_２－または－（Ｃ）＝ＣＨ－で必要に応じて置き換えられており；
ｎは、０、１、２、３、または４であり；そして
ｑは、０、１、２、３、または４である。 As noted above, in another aspect, the present invention provides compounds of formula I-nn:

or a pharma- ceutically acceptable salt thereof, wherein:
Ring M is

Selected from:
Each of X ¹ , X ⁶ and X ⁷ independently represents a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
Each of ^X3 and ^X5 is independently a divalent moiety selected from a covalent bond, _-CR2- , -NR-, -O-, -S-, or _-SiR2- ;
^X4 is

is a trivalent moiety selected from
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R ^3a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) _{2 .} -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -NP(O) _R2 , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR) _NR2 , -N(R)P(O)( _NR2 ) ₂ , or -N(R)S(O) _2R ;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ⁷ is independently hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH)R ₂ , -Si(OH) ₂ R, -SiR ₃ , or an optionally substituted C _1-4 aliphatic; or R ⁷ and X ¹ or X ³ together with the atoms therebetween form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
two R ⁷ groups on the same carbon optionally taken together with the atoms between them form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
two R ⁷ groups on adjacent carbons optionally taken together with the atoms between them form a 3- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
Ring D is selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

As defined above and described herein, each of X ¹ , X ⁶ , and X ⁷ is independently a covalent bond, —CH ₂ —, —C(R) ₂ —, —C(O)—, —C(S)—, —CH(R)—, —CH(CF ₃ )—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR ₂ )—, —S(O)—, —S(O) ₂ —, or
is a divalent moiety selected from

In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently a covalent bond. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -CH ₂ -. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -CR ₂ -. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -C(O)-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -C(S)-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -CH(R)-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -CH(CF ₃ )-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -P(O)(OR)-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -P(O)(R)-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -P(O)NR ₂ -. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -S(O)-. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently -S(O) ₂ -. In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently,
It is.

In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently selected from those depicted in Table 1 below.

As defined above and described herein, ^X2 is a carbon atom, a nitrogen atom, or a silicon atom.

In some embodiments, ^X2 is a carbon atom. In some embodiments, ^X2 is a nitrogen atom. In some embodiments, ^X2 is a silicon atom.

In some embodiments, ^X2 is selected from those depicted in Table 1 below.

As defined above and described herein, X ³ is a divalent moiety selected from -CH ₂ -, -CR ₂ -, -NR-, -CF ₂ -, -CHF-, -S-, -CH(R)-, -SiR ₂ -, or -O-.

In some embodiments, each of X ³ and X ⁵ is independently -CH ₂ -. In some embodiments, each of X ³ and X ⁵ is independently -CR ₂ -. In some embodiments, each of X ³ and X ⁵ is independently -NR-. In some embodiments, each of X ³ and X ⁵ is independently -CF ₂ -. In some embodiments, each of X ³ and X 5 is independently -CHF-. In some embodiments, each of X ³ and X ⁵ is independently -S-. In some embodiments, each of X ³ and X ⁵ is independently -CH(R)-. In some embodiments, each of X ³ and X ⁵ is independently -SiR ₂ -. In some embodiments, ^each of X ³ and X ⁵ is independently -O-.

In some embodiments, each of ^X3 and ^X5 is independently selected from those depicted in Table 1 below.

から選択される三価部分である。 As defined above and described herein, ^X4 is

is a trivalent moiety selected from

In some embodiments, ^X4 is
In some embodiments, ^X4 is
In some embodiments, ^X4 is
In some embodiments, ^X4 is
In some embodiments, ^X4 is
In some embodiments, ^X4 is
In some embodiments, ^X4 is
It is.

In some embodiments, ^X4 is selected from those depicted in Table 1 below.

As defined above and described herein, R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ , optionally substituted C _1-4 aliphatic, or R ¹ and X ¹ or X ⁴ together with the atoms therebetween form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -OR. In some embodiments, R ¹ is -SR. In some embodiments, R ¹ is -S(O)R. In some embodiments, R 1 is -S(O) ₂ R. In some embodiments, R ¹ is -NR _2. In some embodiments, R ¹ is -P(O)(OR) _2. In some embodiments, R ¹ is -P(O)(NR ₂ )OR. In some embodiments, R ¹ is -P(O)(NR ₂ ) _2. In some embodiments, R ¹ is -Si(OH) ₂ R. In some embodiments, R ¹ is -Si(OH)R _2. In some embodiments, R ¹ is -SiR _3. In some embodiments, R ¹ is an optionally substituted C _1-4 aliphatic ^. In some embodiments, R ¹ and X ¹ or X ⁴ together with the atoms between them form a 5- to 7-membered saturated, partially unsaturated, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R ¹ is selected from those depicted in Table 1 below.

As defined above and described herein, each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; or two R groups on the same nitrogen, taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C _1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

As defined above and described herein, each of R ² and R ^3a is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —Si(OH) ₂ R, —Si(OH)R ₂ , —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —C(R) ₂ N(R)C(O)R, —C(R) ₂ N(R)C(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) _{2 .} , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -N(R)P(O)(NR ₂ ) ₂ , or -N(R)S(O) ₂ R.

In some embodiments, R ² and R ^3a are independently hydrogen. In some embodiments, R ^{2 and R 3a are independently -R 6. In some embodiments, R 2 and R 3a are independently halogen. In some embodiments, R 2 and R 3a} are independently -CN. In some embodiments, R ² and R ^{3a are} independently -NO _2. In some embodiments, R ² and R ^3a are independently -OR. In some embodiments, R ² and R ^3a are independently -Si(OH) ₂ R. In some embodiments, R ² and R ^3a are independently -Si(OH)R _2. In some embodiments, R ² and R ^3a are independently -SR. In some embodiments, R ² and R ^3a are independently -NR _2. In some embodiments, R ² and ^{R 3a are} independently -SiR ₃ . In some embodiments, R ² and R ^3a are independently -S(O) ₂ R. In some embodiments, R ² and R ^3a are independently -S(O) ₂ NR _2. In some embodiments, R ² and R ^3a are independently -S(O)R. In some embodiments, R ² and R ^3a are independently -C(O)R. In some embodiments, R ² and R ^3a are independently -C(O)OR. In some embodiments, R ² and R ^3a are independently -C(O)NR _2. In some embodiments, R ² and R ^3a are independently -C(O)N(R)OR. In some embodiments, R ² and R ^3a are independently -C(R) ₂ N(R)C(O)R. In some embodiments, R ² and R ^3a are independently -C(R) ₂ N(R)C(O)NR ₂ . In some embodiments, R ² and R ^3a are independently -OC(O)R. In some embodiments, R ² and R ^3a are independently -OC(O)NR _2. In some embodiments, R ² and R ^3a are independently -OP(O)R _2. In some embodiments, R ² and R ^3a are independently -OP(O)(OR) 2. In some embodiments, R ² and R ^3a are independently -OP(O)(OR)NR _2. In some embodiments, R ² and R ^3a are independently -OP(O)(NR ₂ ) ₂ -. In some embodiments, R 2 and R ^{3a are independently -N(R)C(O)OR. In some embodiments, R 2} _and ^{R 3a} are independently -N(R)C(O)R. In some embodiments, R ² and R ^3a are independently -N(R)C(O)NR _2. In some embodiments, R ² and R ^3a are independently -NP(O)R _2. In some embodiments, R ² and R ^3a are independently -N(R)P(O)(OR) _2. In some embodiments, R ² and R ^3a are independently -N(R)P(O)(OR)NR _2. In some embodiments, R ² and R ^3a are independently -N(R)P(O)(NR ₂ ) _2. In some embodiments, R ² and R ^3a are independently -N(R)S(O) ₂ R.

In some embodiments, R ² and R ^3a are independently -OH. In some embodiments, R ² and R ^3a are independently -NH _2. In some embodiments, R ² and R ^3a are independently -CH ₂ NH _2. In some embodiments, R 2 and R ^3a are independently -CH ₂ NHCOMe. In some embodiments, R ² and R ^3a are independently -CH ₂ NHCONHMe. In some embodiments, R ² and R ^3a are independently -NHCOMe. In some embodiments, R ² and R ^3a are independently -NHCONHEt. In some embodiments, R ² and R ^3a are independently -SiMe _3. In some embodiments, R ² and R ^{3a are} independently -SiMe ₂ OH. In some embodiments, R ² and R ^3a are independently -SiMe(OH) ₂ . In some embodiments, ^R2 and ^R3a are independently
In some embodiments, R ² and R ^3a are independently Br. In some embodiments, R ² and R ^3a are independently Cl. In some embodiments, R 2 and R ^3a are independently F. In some embodiments, R ² and R 3a are independently Me. In some embodiments, R ² and R ^3a are independently -NHMe. In some embodiments, R ² and R ^3a are independently -NMe _2. In some embodiments, R ² and R ^3a are independently -NHCO ₂ Et. In some embodiments, R ² and R ^3a are independently -CN. In some embodiments, R ² and R ^3a are independently -CH ₂ Ph. In some embodiments, R ² and R ^{3a are independently -NHCO 2 tBu. In some embodiments, R 2} _and ^{R 3a are} independently -CO ₂ tBu. In some embodiments, R ² and R ^3a are independently -OMe. In some embodiments, R ² and R ^3a are independently -CF ₃ .

In some embodiments, ^R2 or ^R3a is selected from those depicted in Table 1 below.

As defined above and described herein, R ³ is hydrogen, halogen, —CN, —NO ₂ , —OR, —NR ₂ , —SR, —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR(OR), —OC(O)R, —OC(O)NR ₂ , —OP(O)(OR) ₂ , —OP(O)(NR ₂ ) ₂ , —OP(O)(OR)NR ₂ , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR ₂ , —N(R)S(O) ₂ R, —N(R)S(O) ₂ NR _{2 .} , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR) _NR2 , -P(O)(OR) ₂ , -P(O)( _NR2 )OR, -P(O)( _NR2 ) ₂ , -Si(OH) _2R , -Si(OH)(R) ₂ , or -Si(R) ₃ .

In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is halogen. In some embodiments, R ³ is -CN. In some embodiments, R ³ is -NO _2. In some embodiments, R ³ is -OR. In some embodiments, R 3 is -NR _2. In some embodiments, R ³ is -SR. In some embodiments, R ³ is -S(O) ₂ R. In some embodiments, R ³ is -S(O) ₂ NR _2. In some embodiments, R ³ is -S(O)R. In some embodiments, R ³ is -C(O)R. In some embodiments, R ³ is -C(O)OR. In some embodiments, R ³ is -C(O)NR _2. In some embodiments, R ³ is -C(O)NR(OR). In some embodiments, R ³ is -OC( ^{O)R. In some embodiments, R 3 is} -OC(O)NR ₂ . In some embodiments, R ³ is -OP(O)(OR) _2. In some embodiments, R ³ is -OP(O)(NR ₂ ) _2. In some embodiments, R ³ is -OP(O)(OR)NR _2. In some embodiments, R ³ is -N(R)C(O)R. In some embodiments, R ³ is -N(R)C(O)OR. In some embodiments, R ³ is -N(R)C(O)NR _2. In some embodiments, R ³ is -N(R)S(O) ₂ R. In some embodiments, R ³ is -N(R)S(O) ₂ NR _2. In some embodiments, R ³ is -N(R)P(O)(OR) _2. In some embodiments, R ³ is -N(R)P(O)(OR)NR _2. In some embodiments, R ³ is -P(O)(OR) ₂ . In some embodiments, R ³ is -P(O)(NR ₂ )OR. In some embodiments, R ³ is -P(O)(NR ₂ ) _2. In some embodiments, R ³ is -Si(OH) ₂ R. In some embodiments, R ³ is -Si(OH)(R) _2. In some embodiments, R ³ is -Si(R) ₃ .

In some embodiments, R ³ is methyl. In some embodiments, R ³ is --OCH _3. In some embodiments, R ³ is chloro.

In some embodiments, R ³ is selected from those depicted in Table 1.

As defined above and described herein, each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, or -P(O)(NR ₂ ) ₂ .

In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is -R ^6. In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is -CN. In some embodiments, R ⁴ is -NO _2. In some embodiments, R ⁴ is -OR. In some embodiments, R ⁴ is -SR. In some embodiments, R ⁴ is -NR _2. In some embodiments, R 4 is -S(O) ₂ R. In some embodiments, R ⁴ is -S(O) ₂ NR _2. In some embodiments, R ⁴ is -S(O)R. In some embodiments, R ⁴ is -C(O)R. In some embodiments, R ⁴ is -C(O)OR. In some embodiments, R ⁴ is -C(O)NR _2. In some embodiments, R ⁴ is -C(O)N( ^{R)OR. In some embodiments, R 4 is} -OC(O)R. In some embodiments, R ⁴ is -OC(O)NR _2. In some embodiments, R ^{4 is -N(R)C(O)OR. In some embodiments, R 4} is -N(R)C(O)R. In some embodiments, ^{R 4} is -N(R)C(O)NR _2. In some embodiments, R ⁴ is -N(R)S(O) ₂ R. In some embodiments, R ⁴ is -P(O)(OR) _2. In some embodiments, R ⁴ is -P(O)(NR ₂ )OR. In some embodiments, R ⁴ is -P(O)(NR ₂ ) ₂ .

In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is ethyl. In some embodiments, R ⁴ is cyclopropyl.

In some embodiments, R ⁴ is selected from those depicted in Table 1.

As defined above and described herein, R ⁵ is hydrogen, optionally substituted C _1-4 aliphatic, or —CN.

In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is optionally substituted C _1-4 aliphatic. In some embodiments, R ⁵ is -CN.

In some embodiments, R ⁵ is selected from those depicted in Table 1.

As defined above and described herein, each R ⁶ is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R ⁶ is an optionally substituted C _1-6 aliphatic. In some embodiments, R ⁶ is an optionally substituted phenyl. In some embodiments, R ^{6 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R 6} is ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R ⁶ is selected from those depicted in Table 1.

As generally defined above, each R ⁷ is independently hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O) ₂ R, —N(R) ₂ , —P(O)(R) ₂ , —P(O)(OR) ₂ , —P(O)(NR ₂ )OR, —P(O)(NR ₂ ) ₂ , —Si(OH)R ₂ , —Si(OH) ₂ R, —SiR ₃ , or an optionally substituted C _1-4 aliphatic, or R ¹ and X ¹ or X ³ together with the atoms between them form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or two R 1 on the same carbon are independently selected from the group consisting of 1 to 3 heteroatoms. The ^{R 7} groups optionally combine with the atoms between them to form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or two R ⁷ groups on adjacent carbons optionally combine with the atoms between them to form a 3- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic ring or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R ⁷ is hydrogen. In some embodiments, R ⁷ is halogen. In some embodiments, R ⁷ is -CN. In some embodiments, R ⁷ is -OR. In some embodiments, R ⁷ is -SR. In some embodiments, R ^{7 is -S(O)R. In some embodiments, R 7} is -S(O) ₂ R. In some embodiments, R ⁷ is -NR _2. In some embodiments, R ⁷ is -Si(R) _3. In some embodiments, R ⁷ is -P(O)(R) _2. In some embodiments, R ⁷ is -P(O)(OR) _2. In some embodiments, R ⁷ is -P(O)( ^NR ₂ )OR. In some embodiments, R ⁷ is -P(O)(NR ₂ ) _2. In some embodiments, R ⁷ is -Si ₍ OH)R 2. In some embodiments, R ⁷ is -Si(OH) ₂ R. In some embodiments, R ⁷ is an optionally substituted C _1-4 aliphatic. In some embodiments, R ⁷ and X ¹ or X ³ , together with the atoms between them, form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R ⁷ groups on the same carbon, optionally together with the atoms between them, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R ⁷ groups on adjacent carbons, optionally together with the atoms between them, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R ⁷ groups on adjacent carbons optionally join with the atoms between them to form a 7- to 13-membered saturated, partially unsaturated, bridged, or spiroheterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R ⁷ is selected from hydrogen, halogen, -CN, -OR, -NR ₂ , or C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, halogen, -CN, or C _1-4 alkyl. In some embodiments, R ⁷ is fluoro. In some embodiments, two R ⁷ groups on the same carbon, optionally together with the atoms between them, form a 3- or 4-membered spiro-fused ring.

In some embodiments, R ⁷ is selected from those depicted in Table 1 below.

から選択される二環式環または三環式環である。 As defined above and described herein, Ring A is

is a bicyclic or tricyclic ring selected from:

In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
In some embodiments, Ring A is
It is.

In some embodiments, ring A is selected from those depicted in Table 1 below.

As defined above and described herein, ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

In some embodiments, ring B is a fused 6-membered aryl. In some embodiments, ring B is a fused 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a fused 5-membered to 7-membered, saturated or partially unsaturated carbocyclyl. In some embodiments, ring B is a fused 5-membered to 7-membered, saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring B is a fused 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, Ring B is
In some embodiments, Ring B is
In some embodiments, Ring B is
It is.

In some embodiments, ring B is selected from those depicted in Table 1 below.

から選択される単環式環または二環式環である。 As defined above and described herein, Ring C is

is a monocyclic or bicyclic ring selected from:

In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
It is.

In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
In some embodiments, Ring C is
It is.

から選択される単環式環または二環式環である。 In some embodiments, Ring C is

is a monocyclic or bicyclic ring selected from:

In some embodiments, ring C is selected from those depicted in Table 1 below.

As defined above and described herein, ring D is a ring selected from a 6- to 10-membered aryl or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

In some embodiments, ring D is a 6- to 10-membered aryl. In some embodiments, ring D is a 6- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring D is a 5- to 7-membered saturated or partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, Ring D is phenyl. In some embodiments, Ring D is pyridyl. In some embodiments, Ring D is isoquinoline. In some embodiments, Ring D is imidazo[1,2-a]pyridine.

In some embodiments, ring D is selected from those depicted in Table 1 below.

As defined above and described herein, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where rings E, F, and G are independently optionally substituted with 1 to 2 oxo groups.

In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of rings E, F, and G is independently a fused ring selected from a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring E, ring F, and ring G are independently optionally substituted with 1 to 2 oxo groups.

In some embodiments, ring F is
It is.

In some embodiments, ring E and ring G are independently
In some embodiments, ring E and ring G are independently
In some embodiments, ring E and ring G are independently
In some embodiments, ring E and ring G are independently
In some embodiments, ring E and ring G are independently
It is.

In some embodiments, ring E, ring F, and ring G are
In some embodiments, ring E, ring F, and ring G are
In some embodiments, ring E, ring F, and ring G are
It is.

In some embodiments, rings E, F, and G are selected from those depicted in Table 1 below.

As defined above and described herein, ring H is a ring selected from a 7- to 9-membered, saturated or partially unsaturated, carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where ring E is optionally further substituted with 1 to 2 oxo groups.

In some embodiments, Ring H is a ring selected from a 7- to 9-membered, saturated or partially unsaturated, carbocyclyl ring or a heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring H is optionally further substituted with 1 to 2 oxo groups.

As defined above and described herein, each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, each of rings I and J is independently a 6-membered aryl. In some embodiments, each of rings I and J is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of rings I and J is independently a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of rings I and J is independently a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of rings I and J is independently a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, ring I and ring J are selected from those depicted in Table 1 below.

As defined above and described herein, ring K is a fused ring selected from 7- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where ring H is optionally further substituted with 1 to 2 oxo groups.

In some embodiments, ring K is a fused ring selected from 7-12 membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring K is a 7-12 membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring K is optionally further substituted with 1 to 2 oxo groups.

In some embodiments, ring K is selected from those depicted in Table 1 below.

から選択される。 As defined above and described herein, ring M is

is selected from.

In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
In some embodiments, ring M is
It is.

In some embodiments, ring M is selected from those depicted in Table 1 below.

As defined above and described herein, L ¹ is a covalent bond or a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;

In some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is a C _1-3 aliphatic. In some embodiments, L ¹ is -CH ₂ -. In some embodiments, L ¹ is -C(D)(H)-. In some embodiments, L ¹ is -C(D) ₂ -. In some embodiments, L ¹ is -CH ₂ CH ₂ -. In some embodiments, L ¹ is -NR-. In some embodiments, L 1 is -CH ₂ NR-. In some embodiments, L ¹ is or -O-. In some embodiments, L ¹ is -CH ₂ O-. In some embodiments, L ¹ is -S-. In some embodiments, L ¹ is -OC(O)-. In some embodiments, L ¹ is -C(O)O-. In some embodiments, L ¹ is -C(O)- ^{. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -S} ₍ O)-. In some embodiments, L ¹ is -NRS(O) ₂ -. In some embodiments, L ¹ is -S(O) ₂ NR-. In some embodiments, L ¹ is -NRC(O)-. In some embodiments, L ¹ is -C(O)NR-.

In some embodiments, ring L ¹ is selected from those depicted in Table 1 below.

As defined above and described in embodiments herein,
is a single bond or a double bond.

In some embodiments,
is a single bond. In some embodiments,
is a double bond.

In some embodiments,
is selected from those illustrated in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

In some embodiments, m is selected from those depicted in Table 1 below.

As defined above and described herein, n is 0, 1, 2, 3, or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, n is selected from those depicted in Table 1 below.

As defined above and described herein, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, p is selected from those depicted in Table 1 below.

As defined above and described herein, q is 0, 1, 2, 3, or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

In some embodiments, q is selected from those depicted in Table 1 below.

である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。いくつかの実施形態において、ＬＢＭは、
である。 In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is

In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
It is.

In some embodiments, the LBM is selected from those in Table 1 below.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ａの化合物を提供し、ここでＸ^１、Ｘ^２、Ｘ^３、Ｒ^ａ、Ｒ^ｂ、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、環Ａ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for the preparation of a compound according to the present invention, wherein the LBM is
wherein the compound has formula I-a-1:

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , ^X3 , ^Ra , ^Rb , R1, R2, Rw, ^Rx , ^Ry , ^Rz , L, ^L1 , ^Lx , Ring A, Ring ^W , Ring X, Ring Y, Ring Z, m, ^v , w, x, ^y , and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ａ－１の化合物を提供し、ここでＸ^１、Ｒ^ａ、Ｒ^ｂ、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ａ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds according to formula I-a-2: wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, Ring W is cyclopentyl, and Ring X is pyrazolyl, as shown.

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , R ^a , R ^b , ^R1 , ^R2 , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring A, Ring Y, Ring Z, m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ａの化合物を提供し、ここでＲ^ａ、Ｒ^ｂ、Ｒ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、環Ｄ、環Ｍ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for producing a compound according to the present invention, wherein the LBM is from the formula I-nn
wherein the compound has formula I-a-3:

or a pharma- ceutically acceptable salt thereof, wherein each of R ^a , R ^b , R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ¹ , L ^x , Ring D, Ring M, Ring W, Ring X, Ring Y, Ring Z, n, q, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ａ－３の化合物を提供し、ここでＲ^ａ、Ｒ^ｂ、Ｒ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ｄ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention relates to a compound wherein ring M is
wherein L ¹ is a covalent bond, ring W is cyclopentyl, and ring X is pyrazolyl, and the compound of formula I-a-4:

or a pharma- ceutically acceptable salt thereof, wherein each of R, ^Rb , ^R3a , ^R7 , Rw ^{, Rx} , ^Ry , ^Rz , L, ^Lx , Ring D, Ring Y, Ring Z, n, q, v, w, x, y, and z, ^both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂの化合物を提供し、ここでＸ^１、Ｘ^２、Ｘ^３、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、環Ａ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for the preparation of a compound according to the present invention, wherein the LBM is
wherein the compound has formula I-b-1:

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , X3, R1, R2, ^Rw , ^Rx , ^Ry , ^Rz , L, ^L1 , ^Lx , Ring ^A , Ring W, Ring X, Ring ^Y , Ring ^Z , m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂ－１の化合物を提供し、ここでＸ^１、Ｒ^ａ、Ｒ^ｂ、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ａ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds according to formula I-b-2: where X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, and Ring X is pyrimidinyl, as shown.

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , R ^a , R ^b , ^R1 , ^R2 , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring A, Ring Y, Ring Z, m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂ－１の化合物を提供し、ここでＸ^１、Ｒ^ａ、Ｒ^ｂ、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ａ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds of formula I-b-3, where X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, Ring W is 2-pyridonyl, and Ring X is pyrimidinyl, as shown:

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , R ^a , R ^b , ^R1 , ^R2 , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring A, Ring Y, Ring Z, m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂ－１の化合物を提供し、ここでＸ^１、Ｒ^ａ、Ｒ^ｂ、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ａ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds according to formula I-b-4, where X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, Ring W is 2-pyrrolidonyl, and Ring X is pyrimidinyl, as shown.

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , R ^a , R ^b , ^R1 , ^R2 , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring A, Ring Y, Ring Z, m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂの化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、環Ｄ、環Ｍ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for producing a compound according to the present invention, wherein the LBM is from the formula I-nn
Formula I-b-5:

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, Ry, ^Rz , L, L1, Lx, Ring ^D , Ring ^M , Ring ^W , Ring X, Ring ^Y , Ring ^Z , n, q, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂ－５の化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ｄ、環Ｗ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound wherein ring M is
wherein L ¹ is a covalent bond and ring X is pyrimidinyl, and the compound of formula I-b-6:

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, Ry, ^Rz , L, ^Lx , Ring D, Ring ^W , Ring ^Y , Ring Z, n, q, v, w, x, ^y , and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂ－５の化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ｄ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound wherein ring M is
wherein L ¹ is a covalent bond, ring W is 2-pyridonyl, and ring X is pyrimidinyl;

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, ^Ry , ^Rz , L, ^Lx , Ring D, Ring Y, Ring Z, n, q, v, w, x, ^y , and ^z , both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｂ－５の化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ｄ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound wherein ring M is
wherein L ¹ is a covalent bond, ring W is 2-pyrrolidonyl, and ring X is pyrimidinyl;

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, ^Ry , ^Rz , L, ^Lx , Ring D, Ring Y, Ring Z, n, q, v, w, x, ^y , and ^z , both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｃの化合物を提供し、ここでＸ^１、Ｘ^２、Ｘ^３、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、環Ａ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for the preparation of a compound according to the present invention, wherein the LBM is
Formula I-c-1:

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , X3, R1, R2, ^Rw , ^Rx , ^Ry , ^Rz , L, ^L1 , ^Lx , Ring ^A , Ring W, Ring X, Ring ^Y , Ring ^Z , m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｃ－１の化合物を提供し、ここでＸ^１、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ａ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds according to formula I-c-2: wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, Ring W is phenyl, and Ring X is pyrimidinyl, as shown.

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , ^R1 , ^R2 , Rw, Rx, ^Ry , Rz, L, ^Lx , Ring A, Ring ^Y , Ring Z, m, v, w, ^x , ^y , and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｃの化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、環Ｄ、環Ｍ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for producing a compound according to the present invention, wherein the LBM is from the formula I-nn
Formula I-c-3:

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, Ry, ^Rz , L, ^L1 , Lx, Ring D, Ring ^M , Ring ^W , Ring X, Ring ^Y , Ring ^Z , n, q, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｃ－３の化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、環Ｄ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound wherein ring M is
wherein L ¹ is a covalent bond, ring W is phenyl, and ring X is pyrimidinyl;

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, ^Ry , Rz, L, ^Lx , Ring D, Ring ^Y , Ring Z, n, q, v, w, x, ^y , and ^z , both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｅの化合物を提供し、ここでＸ^１、Ｘ^２、Ｘ^３、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、Ｌ^ｙ、環Ａ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for the preparation of a compound according to the present invention, wherein the LBM is
wherein the compound has formula I-e-1:

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , X3, R1, R2, ^Rw , ^Rx , ^Ry , Rz, L, ^L1 , ^Lx , ^Ly , Ring A, Ring ^W , Ring ^X , Ring ^Y , Ring ^Z , m, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｅ－１の化合物を提供し、ここでＸ^１、Ｒ^１、Ｒ^２、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、Ｌ^ｙ、環Ａ、環Ｙ、環Ｚ、ｍ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds according to formula I-e-2: wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, and Ring X is pyrimidinyl, as shown.

or a pharma- ceutically acceptable salt thereof, wherein each of ^X1 , ^R1 , ^R2 , Rw, Rx, ^Ry , Rz, L, ^Lx , Ly, Ring ^A , Ring ^Y , Ring Z, m, v, w, ^x , ^y , and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｅの化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^１、Ｌ^ｘ、Ｌ^ｙ、環Ｄ、環Ｍ、環Ｗ、環Ｘ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a method for producing a compound according to the present invention, wherein the LBM is from the formula I-nn
wherein the compound has formula I-e-3:

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, Ry, ^Rz , L, ^L1 , Lx, ^Ly , Ring ^D , Ring M, Ring ^W , Ring ^X , Ring Y, Ring ^Z , n, q, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｅ－３の化合物を提供し、ここでＲ^３ａ、Ｒ^７、Ｒ^ｗ、Ｒ^ｘ、Ｒ^ｙ、Ｒ^ｚ、Ｌ、Ｌ^ｘ、Ｌ^ｙ、環Ｄ、環Ｗ、環Ｙ、環Ｚ、ｎ、ｑ、ｖ、ｗ、ｘ、ｙ、およびｚの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound wherein ring M is
wherein L ¹ is a covalent bond and ring X is pyrimidinyl, and the compound of formula I-e-4:

or a pharma- ceutically acceptable salt thereof, wherein each of ^R3a , ^R7 , Rw, Rx, Ry, ^Rz , L, ^Lx , ^Ly , Ring D, Ring ^W , Ring ^Y , Ring ^Z , n, q, v, w, x, y, and z, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物、またはそれぞれ式Ｉ－ｏｏ’－１、Ｉ－ｏｏ’－２、Ｉ－ｏｏ’－３、Ｉ－ｏｏ’－４、Ｉ－ｏｏ’－５、Ｉ－ｏｏ’－６、Ｉ－ｏｏ’－７、Ｉ－ｏｏ’－８、Ｉ－ｏｏ’－９、もしくはＩ－ｏｏ’－１０：

の化合物、またはそれぞれ式Ｉ－ｏｏ’’－１、Ｉ－ｏｏ’’－２、Ｉ－ｏｏ’’－３、Ｉ－ｏｏ’’－４、Ｉ－ｏｏ’’－５、Ｉ－ｏｏ’’－６、Ｉ－ｏｏ’’－７、Ｉ－ｏｏ’’－８、Ｉ－ｏｏ’’－９、もしくはＩ－ｏｏ’’－１０：

の化合物、あるいはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物
、Ｘ、Ｘ_１、Ｘ_２、Ｙ、Ｒ_１、Ｒ_３、Ｒ_３’、Ｒ_４、Ｒ_５、ｔ、ｍおよびｎの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０１７／００７６１２およびＵＳ ２０１８／０１３４６８４で定義および記載されるとおりである。 In certain embodiments, the present invention provides a polypeptide comprising an LBM having the structure represented by Formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9, or I-oo-10, respectively:

or a compound of formula I-oo'-1, I-oo'-2, I-oo'-3, I-oo'-4, I-oo'-5, I-oo'-6, I-oo'-7, I-oo'-8, I-oo'-9, or I-oo'-10, respectively:

or a compound of formula I-oo''-1, I-oo''-2, I-oo''-3, I-oo''-4, I-oo''-5, I-oo''-6, I-oo''-7, I-oo''-8, I-oo''-9, or I-oo''-10, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and the variables
, X, _X1 , _X2 , Y, _R1 , _R3 , _R3 ', _R4 , _R5 , t, m and n are as defined and described in WO 2017/007612 and US 2018/0134684, each of which is incorporated by reference in its entirety.

であり；
Ｙが、結合、Ｙ_１、Ｏ、ＮＨ、ＮＲ_２、Ｃ（Ｏ）Ｏ、ＯＣ（Ｏ）、Ｃ（Ｏ）ＮＲ_２’、ＮＲ_２’Ｃ（Ｏ）、Ｙ_１－Ｏ、Ｙ_１－ＮＨ、Ｙ_１－ＮＲ_２、Ｙ_１－Ｃ（Ｏ）、Ｙ_１－Ｃ（Ｏ）Ｏ、Ｙ_１－ＯＣ（Ｏ）、Ｙ_１－Ｃ（Ｏ）ＮＲ_２’、またはＹ_１－ＮＲ_２’Ｃ（Ｏ）であり、ここでＹ_１は、Ｃ_１～Ｃ_６アルキレン、Ｃ_２～Ｃ_６アルケニレン、またはＣ_２～Ｃ_６アルキニレンであり；
Ｘが、Ｃ（Ｏ）またはＣ（Ｒ_３）_２であり；
Ｘ_１－Ｘ_２が、Ｃ（Ｒ_３）＝ＮまたはＣ（Ｒ_３）_２－Ｃ（Ｒ_３）_２であり；
各Ｒ_１が独立して、ハロゲン、ニトロ、ＮＨ_２、ＯＨ、Ｃ（Ｏ）ＯＨ、Ｃ_１～Ｃ_６アルキル、またはＣ_１～Ｃ_６アルコキシであり；
Ｒ_２が、Ｃ_１～Ｃ_６アルキル、Ｃ_２～Ｃ_６アルケニル、Ｃ_３～Ｃ_８シクロアルキル、３員～８員のヘテロシクロアルキル、Ｃ（Ｏ）－Ｃ_１～Ｃ_６アルキル、Ｃ（Ｏ）－Ｃ_２～Ｃ_６アルケニル、Ｃ（Ｏ）－Ｃ_３～Ｃ_８シクロアルキル、またはＣ（Ｏ）－３員～８員のヘテロシクロアルキルであり、そしてＲ_２は、ハロゲン、Ｎ（Ｒ_ａ）_２、ＮＨＣ（Ｏ）Ｒ_ａ、ＮＨＣ（Ｏ）ＯＲ_ａ、ＯＲ_ｂ、Ｃ_３～Ｃ_８シクロアルキル、３員～８員のヘテロシクロアルキル、Ｃ_６～Ｃ_１０アリール、または５員～１０員のヘテロアリールのうちの１つまたはそれより多くで必要に応じて置換されており、ここでこのＣ_３～Ｃ_８シクロアルキル、３員～８員のヘテロシクロアルキル、Ｃ_６～Ｃ_１０アリールまたは５員～１０員のヘテロアリールの各々は、ハロゲン、ＮＨ_２、ＣＮ、ニトロ、ＯＨ、Ｃ（Ｏ）ＯＨ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６アルコキシ、またはＣ_１～Ｃ_６ハロアルコキシのうちの１つまたはそれより多くで必要に応じてさらに置換されており；
Ｒ_２’が、Ｈ、Ｃ_１～Ｃ_６アルキル、Ｃ_２～Ｃ_６アルケニル、Ｃ_３～Ｃ_８シクロアルキル、または３員～８員のヘテロシクロアルキルであり、そしてＲ_２’は、Ｈではない場合、ハロゲン、Ｎ（Ｒ_ａ）_２、ＮＨＣ（Ｏ）Ｒ_ａ、ＮＨＣ（Ｏ）ＯＲ_ａ、ＯＲ_ｂ、Ｃ_３～Ｃ_８シクロアルキル、３員～８員のヘテロシクロアルキル、Ｃ_６～Ｃ_１０アリール、または５員～１０員のヘテロアリールのうちの１つまたはそれより多くで必要に応じて置換されており、ここでこのＣ_３～Ｃ_８シクロアルキル、３員～８員のヘテロシクロアルキル、Ｃ_６～Ｃ_１０アリールまたは５員～１０員のヘテロアリールの各々は、ハロゲン、ＮＨ_２、ＣＮ、ニトロ、ＯＨ、Ｃ（Ｏ）ＯＨ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６アルコキシ、またはＣ_１～Ｃ_６ハロアルコキシのうちの１つまたはそれより多くで必要に応じてさらに置換されており；
各Ｒ_３が独立して、Ｈ、またはＣ_６～Ｃ_１０アリールもしくは５員～１０員のヘテロアリールで必要に応じて置換されたＣ_１～Ｃ_３アルキルであり；
各Ｒ_３’が独立して、Ｃ_１～Ｃ_３アルキルであり；
各Ｒ_４が独立して、ＨまたはＣ_１～Ｃ_３アルキルであるか；あるいは２個のＲ_４は、これらが結合している炭素原子と一緒になって、Ｃ（Ｏ）、Ｃ_３～Ｃ_６炭素環、またはＮおよびＯから選択される１個もしくは２個のヘテロ原子を含む４員、５員、もしくは６員の複素環を形成し；
Ｒ_５が、Ｈ、Ｃ_１～Ｃ_３アルキル、Ｆ、またはＣｌであり；
各Ｒ_ａが独立して、ＨまたはＣ_１～Ｃ_６アルキルであり；
Ｒ_ｂが、Ｈまたはトシルであり；
ｔが、０または１であり；
ｍが、０、１、２または３であり；そして
ｎが、０、１または２である、
式Ｉ－ｏｏ－１、Ｉ－ｏｏ－２、Ｉ－ｏｏ－３、Ｉ－ｏｏ－４、Ｉ－ｏｏ－５、Ｉ－ｏｏ－６、Ｉ－ｏｏ－７、Ｉ－ｏｏ－８、Ｉ－ｏｏ－９、Ｉ－ｏｏ－１０、Ｉ－ｏｏ’－１、Ｉ－ｏｏ’－２、Ｉ－ｏｏ’－３、Ｉ－ｏｏ’－４、Ｉ－ｏｏ’－５、Ｉ－ｏｏ’－６、Ｉ－ｏｏ’－７、Ｉ－ｏｏ’－８、Ｉ－ｏｏ’－９、Ｉ－ｏｏ’－１０、Ｉ－ｏｏ’’－１、Ｉ－ｏｏ’’－２、Ｉ－ｏｏ’’－３、Ｉ－ｏｏ’’－４、Ｉ－ｏｏ’’－５、Ｉ－ｏｏ’’－６、Ｉ－ｏｏ’’－７、Ｉ－ｏｏ’’－８、Ｉ－ｏｏ’’－９、もしくはＩ－ｏｏ’’－１０の化合物、またはその薬学的に受容可能な塩を提供する。 Thus, in some embodiments, the present invention provides a method for producing
but

and
Y is a bond, Y ₁ , O, NH, NR ₂ , C(O)O, OC(O), C(O)NR ₂ ', NR ₂ 'C(O), Y ₁ -O, Y ₁ -NH, Y ₁ -NR ₂ , Y ₁ -C(O), Y ₁ -C(O)O, Y ₁ -OC(O), Y ₁ -C(O)NR ₂ ', or Y ₁ -NR ₂ 'C(O), where Y ₁ is a C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene;
X is C(O) or C( _R3 ) ₂ ;
X ₁ -X ₂ are C(R ₃ )═N or C(R ₃ ) ₂ -C(R ₃ ) ₂ ;
each R ₁ is independently halogen, nitro, NH ₂ , OH, C(O)OH, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy;
R ₂ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl, C(O)-C ₃ -C ₈ cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R ₂ is optionally substituted with one or more of halogen, N(R _a ) ₂ , NHC(O)R _a , NHC(O)OR _a , OR _b , C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, where the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C Each of the ₁₀ aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH ₂ , CN, nitro, OH, C(O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ haloalkoxy;
R ₂ ' is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, or 3- to 8-membered heterocycloalkyl, and when R ₂ ' is not H, it is optionally substituted with one or more of halogen, N(R _a ) ₂ , NHC(O)R _a , NHC(O)OR _a , OR _b , C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, where each of said C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is halogen, NH ₂ , CN, nitro, OH, C(O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C Optionally further substituted with one or more of C ₁ -C 6 alkoxy, or C ₁ -C ₆ haloalkoxy;
each R ₃ is independently H, or C ₁ -C ₃ alkyl optionally substituted with C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl;
each R ₃ ' is independently C ₁ -C ₃ alkyl;
Each R ₄ is independently H or C ₁ -C ₃ alkyl; or two R ₄ together with the carbon atom to which they are attached form a C(O), a C ₃ -C ₆ carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O;
R ₅ is H, C ₁ -C ₃ alkyl, F, or Cl;
Each R _a is independently H or C ₁ -C ₆ alkyl;
R _b is H or tosyl;
t is 0 or 1;
m is 0, 1, 2 or 3; and n is 0, 1 or 2;
Provided are compounds of formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9, I-oo-10, I-oo'-1, I-oo'-2, I-oo'-3, I-oo'-4, I-oo'-5, I-oo'-6, I-oo'-7, I-oo'-8, I-oo'-9, I-oo'-10, I-oo''-1, I-oo''-2, I-oo''-3, I-oo''-4, I-oo''-5, I-oo''-6, I-oo''-7, I-oo''-8, I-oo''-9, or I-oo''-10, or a pharma- ceutically acceptable salt thereof.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ａ、Ｇ、Ｇ’、Ｑ_１、Ｑ_２、Ｑ_３、Ｑ_４、Ｒ、Ｒ’、Ｗ、Ｘ、Ｙ、Ｚ、
、およびｎの各々は、その各々の全体が本明細書中に参考として援用される、ＷＯ ２０１６／１９７１１４およびＵＳ ２０１８／０１４７２０２で定義および記載されるとおりである。 In certain embodiments, the present invention provides peptides wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula I-pp-1, I-pp-2, I-pp-3, I-pp-4, I-pp-5, or I-pp-6, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and the variables A, G, G', _Q1 , _Q2 , _Q3 , _Q4 , R, R', W, X, Y, Z,
, and n are as defined and described in WO 2016/197114 and US 2018/0147202, each of which is incorporated by reference in its entirety.

In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
It is.

In some embodiments, the LBM is selected from those in Table 1 below.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^１０、Ｒ^１１、Ｒ^１４、Ｒ^１７、Ｗ^１、Ｗ^２、Ｘ、

、およびｎの各々は、その全体が本明細書中に参考として援用されるＷＯ ２０１７／１９７０５１で定義されるとおりであり、そして
は、Ｒ^１、Ｒ^１とＲ^２とを合わせることにより形成される環、またはＲ^１７に、ＷＯ ２０１７／１９７０５１で定義されるＲ^１２の結合部位で結合しており、その結果、
がＲ^１２置換基の代わりとなる。 In certain embodiments, the present invention provides a method for the treatment of cancer, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby representing the formula I-qq-1, I-qq-2, or I-qq-3, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and the variables ^R1 , ^R2 , ^R4 , R5, ^R10 , ^R11 , ^R14 , ^R17 , ^W1 , ^W2 , ^X ,

each of n is as defined in WO 2017/197051, the entirety of which is incorporated herein by reference; and
is attached to R ¹ , the ring formed by combining R ¹ and R ² , or R ¹⁷ at the attachment site of R ¹² as defined in WO 2017/197051, such that
replaces the R ¹² substituent.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^４、Ｒ^１０、Ｒ^１１、Ｒ^１４、Ｒ^１６、Ｗ^１、Ｗ^２、Ｘ、

、およびｎの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１８／２３７０２６で定義されるとおりであり、そして
は、Ｒ^１またはＲ^１６に、ＷＯ ２０１８／２３７０２６で定義されるＲ^１２の結合部位で結合しており、その結果、
がＲ^１２置換基の代わりとなる。 In some embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon) binding moiety, the LBM being represented by formula I-rr-1, I-rr-2, I-rr-3, or I-rr-4, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and the variables ^R1 , ^R4 , ^R10 , ^R11 , R14, ^R16 , ^W1 , ^{W2 ,} X,

and each of n is as defined in WO 2018/237026, each of which is incorporated by reference in its entirety; and
is attached to R ¹ or R ¹⁶ at the attachment site of R ¹² as defined in WO 2018/237026, such that
replaces the R ¹² substituent.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^１４、およびＲ^１６の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１８／２３７０２６で定義されるとおりであり、そして
は、Ｒ^１またはＲ^１６に、ＷＯ ２０１８／２３７０２６で定義されるＲ^１２の結合部位で結合しており、その結果、
がＲ^１２置換基の代わりとなる。 In some embodiments, the present invention provides a method for the preparation of ubiquitin ligase (cereblon) binding moieties, which are represented by formula I-ss-1 or I-ss-3, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and each of the variables ^R1 , ^R14 , and ^R16 are as defined in WO 2018/237026, each of which is incorporated herein by reference in its entirety; and
is attached to R ¹ or R ¹⁶ at the attachment site of R ¹² as defined in WO 2018/237026, such that
replaces the R ¹² substituent.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ａｒ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ａ、Ｌ、ｘ、ｙ、および

の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１７／１６１１１９に記載および定義されるとおりである。 In certain embodiments, the present invention provides an LBM that is an E3 ubiquitin ligase (cereblon) binding moiety, thereby comprising the formula I-tt-1, I-tt-2, I-tt-3, I-tt-4, I-tt-5, I-tt-6, I-tt-7, or I-tt-8:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and the variables Ar ^{, R1} , ^R2 , ^R3 , R4, ^R5 , ^R6 , ^R7 , ^R8 , A, L, x, y, and

each as described and defined in WO 2017/161119, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ａ、Ｂ、Ｃ、Ｗ、Ｘ、Ｙ、およびＺの各々は、その各々の全体が本明細書中に参考として援用されるＵＳ ５，７２１，２４６に記載および定義されるとおりである。 In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, the ubiquitin ligase having the formula I-uu:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in embodiments herein, and each of the variables A, B, C, W, X, Y, and Z are as described and defined in U.S. Pat. No. 5,721,246, each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ_１、Ｒ_２、およびｎの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１９／０４３２１４に記載および定義されるとおりである。 In certain embodiments, the present invention provides a polypeptide comprising an LBM that is an E3 ubiquitin ligase (cereblon) binding moiety, such as that represented by formula I-vv:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in embodiments herein, and each of the variables _R1 , _R2 , and n are as described and defined in WO 2019/043214, each of which is incorporated herein by reference in its entirety.

であり、ここで
は、修飾可能な炭素原子、酸素原子、窒素原子または硫黄原子に結合している。 In some embodiments, the LBM comprises an IAP E3 ubiquitin ligase binding moiety as described in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4):669-81, such as:

where
is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１’、Ｒ^２’、Ｒ^３’、Ｘ、およびＸ’の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１３／１０６６４３およびＵＳ ２０１４／０３５６３２２で定義および記載されるとおりである。 In certain embodiments, the invention provides a method for the treatment of VHL E3 ubiquitin ligase-binding moiety comprising administering to a patient a therapeutically effective amount of the LBM, the method comprising administering to a patient a therapeutically effective amount of the LBM comprising administering to a patient a therapeutically effective amount of the LBM

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables R1 ^' , R2 ^' , R3 ^' , X, and X' are as defined and described in WO 2013/106643 and US 2014/0356322, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１’、Ｒ^２’、Ｒ^３’、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_９、Ｒ_１０、Ｒ_１１、Ｒ_１４、Ｒ_１５、Ｒ_１６、Ｒ_１７、Ｒ_２３、Ｒ_２５、Ｅ、Ｇ、Ｍ、Ｘ、Ｘ’、Ｙ、Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、およびｏの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１６／１４９６６８およびＵＳ ２０１６／０２７２６３９で定義および記載されるとおりである。 In certain embodiments, the invention provides a method for the preparation of a VHL E3 ubiquitin ligase binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase binding moiety having the structure of formula I-xx-1, I-xx-2, I-xx-3, I-xx-4, I-xx-5, or I-xx-6, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables R1 ^' , R2 ^' , R3 ^' , R5, _R6 , _R7 , _R9 , R10, _R11 , _R14 , _R15 , _R16 , _R17 , _R23 , _R25 , E, G, M, X, X', Y, _Z1 , _Z2 , _Z3 , _Z4 , and _o are as defined and described in WO _2016/149668 and US 2016/0272639, each of which is incorporated by reference in its entirety.

。 As used herein, the description of brackets surrounding any LBM
Box's
This means that the moiety is covalently attached to the LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom. For clarity and by way of example, such available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structures are illustrated below, where each wavy bond represents the
Specify an attachment point to:

.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^ｐ、Ｒ_９、Ｒ_１０、Ｒ_１１、Ｒ_１４ａ、Ｒ_１４ｂ、Ｒ_１５、Ｒ_１６、Ｗ^３、Ｗ^４、Ｗ^５、Ｘ^１、Ｘ^２、およびｏの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１６／１１８６６６およびＵＳ ２０１６／０２１４９７２で定義および記載されるとおりである。 In certain embodiments, the invention provides a method for the preparation of a VHL E3 ubiquitin ligase binding moiety, whereby the LBM is a VHL E3 ubiquitin ligase binding moiety represented by formula I-yy-1, I-yy-2, or I-yy-3, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^Rp , _R9 , _R10 , _R11 , _R14a , _R14b , _R15 , _R16 , ^W3 , ^W4 , ^W5 , ^X1 , ^X2 , and o are as defined and described in WO 2016/118666 and US 2016/0214972, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ａ^１、Ａ^２、Ａ^３、Ｒ^５、ＧおよびＺの各々は、ＷＯ ２０１７／１７６９５８で定義および記載されるとおりである。 In certain embodiments, the invention provides methods wherein the LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety, thereby representing formula I-zz-1, I-zz-2, I-zz-3, I-zz-4, I-zz-5, I-zz-6, or I-zz-7, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^A1 , ^A2 , ^A3 , ^R5 , G and Z are as defined and described in WO 2017/176958.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ａ^１、Ａ^２、Ａ^３、Ｒ^５、ＧおよびＺの各々は、その全体が本明細書中に参考として援用されるＷＯ ２０１７／１７６９５８で定義および記載されるとおりである。 In certain embodiments, the present invention provides methods for treating cancer, wherein the LBM is a CRBN E3 ubiquitin ligase binding moiety, thereby having the formula I-zz'-1, I-zz''-1, I-zz'-2, I-zz'-2, I-zz'-3, I-zz''-3, I-zz'-4, I-zz''-4, I-zz'-7, or I-zz''-7, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^A1 , ^A2 , ^A3 , ^R5 , G and Z are as defined and described in WO 2017/176958, the entirety of which is incorporated herein by reference.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、Ｒ_９、Ｒ_１０、Ｒ_１１、Ｒ_１２、Ｒ_１３、Ｒ_１４、Ｒ_１５、Ｒ_１６、Ｒ_１７、Ｒ_１８、Ｒ_１９、Ｒ_２０、Ｒ_２１、Ｒ_２２、Ｒ_２３、Ｒ_２４、Ｒ_２５、Ｒ_２６、Ｒ_２７、Ｒ_２８、Ｒ_１’、Ｒ_２’、Ｒ_３’、Ｒ_４’、Ｒ_５’、Ｒ_６’、Ｒ_７’、Ｒ_８’、Ｒ_９’、Ｒ_１０’、Ｒ_１１’、Ｒ_１２’、Ｒ_１’’、Ａ、Ａ’、Ａ’’、Ｘ、Ｙ、およびＺの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１７／０１１３７１およびＵＳ ２０１７／０００８９０４で定義および記載されるとおりである。 In certain embodiments, the present invention provides that the LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby representing a sequence of formula I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17, or I-aaa-18, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and the variables _R1 , _R2 , R3, R4, R5, R6, R7, R8, R9, R10, _R11 , _R12 , _R13 , _R14 , _R15 , _R16 , _R17 , _R18 , _R19 , _R20 , _R21 , _R22 , _R23 , _{R24 , R25, R26 , R27 , R28 ,} R1 _' , R2 _' , R3 _' , _{R4 '} , _{R5 '} , _{R6 '} , _{R7 '} , _{R8' ,} R Each of R _9' , R _10' , R _11' , R _12' , R _1'' , A, A', A'', X, Y, and Z are as defined and described in WO 2017/011371 and US 2017/0008904, each of which is incorporated by reference in its entirety herein.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここで可変物Ｒ^１２ｃ、Ｒ^１２ｄ、Ｒ^１３、Ｒ^１７、Ｒ^１８ｂ、Ｒ^１８ｃ、Ｒ^１８ｄ、Ａ^５、Ａ^６、Ａ^７、Ｑ^１、およびＡｒの各々は、ＷＯ ２０１７／１７６９５７およびＵＳ２０１９／１２７３８７で定義および記載されるとおりである。 In certain embodiments, the present invention provides a method for the preparation of a medicament for the treatment of a pulmonary fibrosis, comprising administering to a patient a medicament for the treatment of a pulmonary fibrosis, the method ...

or a pharma- ceutically acceptable salt thereof, wherein each of the variables ^R12c , ^R12d , R13, ^R17 , ^R18b , ^R18c , ^R18d , ^{A5 , A6} , ^A7 , ^Q1 , and Ar are as defined and described in WO 2017/176957 and US2019/127387.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、およびＲ^７の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１７／０１１５９０およびＵＳ ２０１７／００３７００４で定義および記載されるとおりである。 In certain embodiments, the invention provides an IAP E3 ubiquitin ligase binding moiety, thereby having the formula I-bbb-1, I-bbb-2, I-bbb-3, or I-bbb-4, respectively:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , and ^R7 are as defined and described in WO 2017/011590 and US 2017/0037004, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載される通りであり、そして：
Ｘ^１、Ｘ^２ａ、およびＸ^３ａの各々は独立して、共有結合、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｘ^４ａおよびＸ^５ａの各々は独立して、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
から選択される二価部分であり；
Ｒ^１は、水素、ハロゲン、－ＣＮ、－ＯＲ、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）_２Ｒ、－ＮＲ_２、または必要に応じて置換されたＣ_１～４脂肪族であり；
Ｒ^２、Ｒ^３ｂ、およびＲ^４ａの各々は独立して、水素、－Ｒ^６、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、または－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒであり；
Ｒ^５ａは、水素またはＣ_１～６脂肪族であり；
各Ｒ^６は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基であり；
環Ａ^ａは、０個～２個の窒素原子を含む６員アリール、５員～７員の部分飽和カルボシクリル、窒素、酸素もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する５員～７員の部分飽和ヘテロシクリル、または窒素、酸素もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員ヘテロアリールから選択される縮合環であり；
環Ｂ^ａは、０個～２個の窒素原子を含む６員アリール、または窒素、酸素、もしくは硫黄から独立して選択される１個～５個のヘテロ原子を有する８員～１０員の二環式ヘテロアリールから選択され；
環Ｃ^ａは、０個～２個の窒素原子を含む６員アリール、または窒素、酸素もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する５員ヘテロアリールから選択され；
ｍは、０、１、２、３または４であり；
ｏは、０、１、２、３または４であり；
ｑは、０、１、２、３または４であり；そして
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素原子上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成する。 In certain embodiments, the invention provides compounds wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; thereby represented by formula I-ccc-1, I-ccc-2, or I-ccc-3:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and
Each of X ¹ , X ^2a and X ^3a independently represents a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
Each of X ^4a and X ^5a independently represents -CH ₂ -, -C(O)-, -C(S)-, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic;
each of R ² , R ^3b , and R ^4a is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
R ^5a is hydrogen or C _1-6 aliphatic;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring A ^a is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B ^a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring C ^a is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0, 1, 2, 3 or 4;
o is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3, or 4; and each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
Two R groups on the same nitrogen atom, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉ－ｃｃｃ－１の化合物を提供し、ここでＣＢＭ、Ｌ、環Ａ^ａ、Ｘ^１、Ｘ^２ａ、Ｘ^３ａ、Ｒ^１、Ｒ^２およびｍは、上に記載されたとおりである。 In certain embodiments, the present invention provides a method for the preparation of a compound according to the invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby having the formula I-ccc'-1 or I-ccc''-1:

or a pharma- ceutically acceptable salt thereof, wherein CBM, L, ring ^Aa , ^X1 , ^X2a , ^X3a , ^R1 , ^R2 and m are as described above.

As defined above and described herein, each of X ¹ , X ^2a , and X ^3a is independently a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from

In some embodiments, X ¹ is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
It is.

In some embodiments, X ¹ is selected from those depicted in Table 1 below.

In some embodiments, X ^2a is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
It is.

In some embodiments, X ^2a is selected from those depicted in Table 1 below.

In some embodiments, X ^3a is a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
It is.

In some embodiments, X ^3a is selected from those depicted in Table 1 below.

As defined above and described herein, each of X ⁴ and X ⁵ is independently —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from

In some embodiments, X ^4a is —CH ₂ —, —C(O)—, —C(S)—, or
It is.

In some embodiments, X ^4a is selected from those depicted in Table 1 below.

In some embodiments, X ^5a is —CH ₂ —, —C(O)—, —C(S)—, or
It is.

In some embodiments, X ^5a is selected from those depicted in Table 1 below.

As defined above and described herein, R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic.

In some embodiments, R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic.

In some embodiments, R ¹ is selected from those depicted in Table 1 below.

As defined above and described herein, each of R ² , R ^3b , and R ^4a is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R.

In some embodiments, R ² is hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R.

In some embodiments, ^R2 is selected from those depicted in Table 1 below.

In some embodiments, R ^3b is hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R.

In some embodiments, R ^3b is methyl.

In some embodiments, R ^3b is selected from those depicted in Table 1 below.

In some embodiments, R ^4a is hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R.

In some embodiments, R ^4a is methyl.

In some embodiments, R ^4a is selected from those depicted in Table 1 below.

As defined above and described herein, R ^5a is hydrogen or C _1-6 aliphatic.

In some embodiments, R ^5a is t-butyl.

In some embodiments, R ^5a is selected from those depicted in Table 1 below.

As defined above and described herein, each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ⁶ is an optionally substituted C _1-6 aliphatic group. In some embodiments, R ⁶ is an optionally substituted phenyl. In some embodiments, R ⁶ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁶ is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ⁶ is selected from those depicted in Table 1 below.

As defined above and described herein, Ring A ^a is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, ring A ^a is a fused 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, ring A ^a is a fused 5- to 7-membered partially saturated carbocyclyl. In some embodiments, ring A ^a is a fused 5- to 7-membered partially saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A ^a is a fused 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A ^a is a fused phenyl.

In some embodiments, Ring A ^a is selected from those depicted in Table 1 below.

As defined above and described herein, Ring B ^a is selected from a 6-membered aryl containing 0-2 nitrogen atoms, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring B ^a is a 6-membered aryl containing 0-2 nitrogen atoms, In some embodiments, Ring B ^a is an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring B ^a is
It is.

In some embodiments, Ring B ^a is selected from those depicted in Table 1 below.

As defined above and described herein, Ring C ^a is selected from a 6-membered aryl containing 0-2 nitrogen atoms, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring C ^a is a 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, Ring C ^a is a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring C ^a is
It is.

In some embodiments, Ring C ^a is selected from those depicted in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3, or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

In some embodiments, m is selected from those depicted in Table 1 below.

In some embodiments, o is selected from those depicted in Table 1 below.

As defined above and described herein, o is 0, 1, 2, 3, or 4.

In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

In some embodiments, o is selected from those depicted in Table 1 below.

As defined above and described herein, q is 0, 1, 2, 3, or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

In some embodiments, q is selected from those depicted in Table 1 below.

As defined above and described herein, each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen atom, optionally combined with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen atom, optionally together with atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ_９、Ｒ_１０、Ｒ_１１、Ｒ_１４ａ、およびＲ_１５の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１７／０３０８１４、ＷＯ ２０１６／１１８６６６、およびＵＳ ２０１７／０３２７４６９に記載および定義されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is a VHL binding moiety, whereby the compound has the formula I-ddd:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in embodiments herein, and each of the variables _R9 , _R10 , _R11 , _R14a , and _R15 are as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, each of which is incorporated by reference in its entirety.

In certain embodiments, the present invention provides a compound wherein the LBM is a VHL binding moiety, whereby the compound has formula I-eee-1 or I-eee-2:
or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in embodiments herein, and each of the variables X, W, _R9 , _R10 , _R11 , _R14a , and _R14b , _R15 , ^R16 , and o are as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｗ、Ｙ、Ｚ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１４／０４４６２２、ＵＳ ２０１５／０２２５４４９。ＷＯ ２０１５／０７１３９３、およびＵＳ ２０１６／０２７２５９６に記載および定義されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is an IAP binding moiety, thereby having the formula I-fff:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables W, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , and ^R5 are as described and defined in WO 2014/044622, US 2015/0225449, WO 2015/071393, and US 2016/0272596, each of which is incorporated by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載される通りであり、その各々の全体が本明細書中に参考として援用されるＨｉｎｅｓ，Ｊ．ｅｔ ａｌ．，Ｃａｎｃｅｒ Ｒｅｓ．（ＤＯＩ：１０．１１５８／０００８－５４７２．ＣＡＮ－１８－２９１８）に記載および定義されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is an MDM2 binding moiety, whereby the compound has the formula I-ggg:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in the embodiments herein, and as described and defined in Hines, J. et al., Cancer Res. (DOI:10.1158/0008-5472.CAN-18-2918), each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載される通りであり、その各々の全体が本明細書中に参考として援用されるＺｈａｎｇ，Ｘ．ｅｔ ａｌ．，ｂｉｏＲｘｉｖ（ｄｏｉ：ｈｔｔｐｓ：／／ｄｏｉ．ｏｒｇ／１０．１１０１／４４３８０４）に記載および定義されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is a DCAF16 binding moiety, thereby having the formula I-hhh:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in the embodiments herein, and as described and defined in Zhang, X. et al., bioRxiv (doi:https://doi.org/10.1101/443804), each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載される通りであり、その各々の全体が本明細書中に参考として援用されるＳｐｒａｄｉｎ，Ｊ．Ｎ．ｅｔ ａｌ．，ｂｉｏＲｘｉｖ（ｄｏｉ：ｈｔｔｐｓ：／／ｄｏｉ．ｏｒｇ／１０．１１０１／４３６９９８）に記載および定義されるとおりである。 In certain embodiments, the present invention provides compounds wherein the LBM is an RNF114 binding moiety, whereby the compound has formula I-iii:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and as described and defined in Spradin, J. N. et al., bioRxiv (doi:https://doi.org/10.1101/436998), each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載される通りであり、その各々の全体が本明細書中に参考として援用されるＷａｒｄ，Ｃ．Ｃ．，ｅｔ ａｌ．，ｂｉｏＲｘｉｖ（ｄｏｉ：ｈｔｔｐｓ：／／ｄｏｉ．ｏｒｇ／１０．１１０１／４３９１２５）に記載および定義されるとおりである。 In certain embodiments, the present invention provides compounds wherein the LBM is an RNF4 binding moiety, whereby the compound has formula I-jjj:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in the embodiments herein, and as described and defined in Ward, C. C., et al., bioRxiv (doi:https://doi.org/10.1101/439125), each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^２、Ｒ^３、Ｘ、およびＹの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１９／０８４０２６で定義および記載されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is a VHL binding moiety, thereby having the formula I-nnn-1 or I-nnn-2:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R2 , ^R3 , X, and Y are as defined and described in WO 2019/084026, each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ^１、Ｒ^３、およびＹの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１９／０８４０３０で定義および記載されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is a VHL binding moiety, thereby comprising the compound of formula I-ooo-1 or I-ooo-2:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R3 , and Y are as defined and described in WO 2019/084030, each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中に記載されるとおりであり、そして可変物Ｒ^４、Ｒ^１０、Ｒ^１１、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｗ^１、Ｗ^２、およびＸの各々は、その全体が本明細書中に参考として援用されるＷＯ ２０１９／０９９８６８で定義されるとおりであり、そして
は、Ｒ^１７またはＲ^１６に、ＷＯ ２０１８／２３７０２６で定義されるＲ^１２の結合部位で結合しており、その結果、
がＲ^１２置換基の代わりとなる。 In certain embodiments, the present invention provides a polypeptide comprising an LBM having the formula I-ppp-1, I-ppp-2, I-ppp-3, or I-ppp-4:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and each of the variables ^R4 , ^R10 , ^R11 , ^R15 , ^R16 , ^R17 , ^W1 , ^W2 , and X are as defined in WO 2019/099868, the entirety of which is incorporated herein by reference; and
is attached to R ¹⁷ or R ¹⁶ at the attachment site of R ¹² as defined in WO 2018/237026, such that
replaces the R ¹² substituent.

In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
It is.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、ここで：
各Ｘ^１は独立して、

であり；
Ｘ^２およびＸ^３は独立して、－ＣＨ_２－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、または
であり；
Ｚ^１およびＺ^２は独立して、炭素原子または窒素原子であり；
環Ａは、ベンゾ、窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有する４員～６員の飽和もしくは部分不飽和の炭素環式、もしくは複素環式の環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される縮合環であり；
Ｌ^１は、共有結合、またはＣ_１～３の二価の直鎖もしくは分枝鎖の、飽和もしくは不飽和の炭化水素鎖であり、ここでこの鎖の１個～２個のメチレン単位は独立して、－Ｏ－、－Ｓ－、－Ｃ（Ｏ）－、－Ｃ（Ｓ）－、－ＣＲ_２－、－ＣＲＦ－、－ＣＦ_２－、－ＮＲ－、または－Ｓ（Ｏ）_２－で必要に応じて置き換えられており；
各Ｒ^１は独立して、水素、Ｒ^４、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－ＣＦ_２Ｒ、－ＣＲ_２Ｆ、－ＣＦ_３、－ＣＲ_２（ＯＲ）、－ＣＲ_２（ＮＲ_２）、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｃ（Ｓ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２、－Ｓｉ（ＯＲ）Ｒ_２、および－ＳｉＲ_３から選択されるか；あるいは
２個のＲ^１基は、必要に応じて一緒になって、窒素、酸素、または硫黄から独立して選択される０個～２個のヘテロ原子を有する、必要に応じて置換された５員～８員の部分不飽和またはアリールの縮合環を形成し；
各Ｒは独立して、水素、または必要に応じて選択された基から選択され、この必要に応じて選択された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ炭素または窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この炭素または窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する、必要に応じて置換された４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し；
Ｒ^２は、
または水素から選択され；
環Ｂは、フェニル、４員～１０員の飽和または部分不飽和の、単環式または二環式の、炭素環式環、または窒素、酸素、および硫黄から独立して選択される１個～３個のヘテロ原子を有する複素環式環、あるいは窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環であり、ここで環Ｂは、１個～２個のオキソ基で必要に応じてさらに置換されており；
各Ｒ^３は独立して、水素、Ｒ^４、ハロゲン、－ＣＮ、－ＮＯ_２、－ＯＲ、－ＳＲ、－ＮＲ_２、－Ｓ（Ｏ）_２Ｒ、－Ｓ（Ｏ）_２ＮＲ_２、－Ｓ（Ｏ）Ｒ、－ＣＦ_２Ｒ、－ＣＦ_３、－ＣＲ_２（ＯＲ）、－ＣＲ_２（ＮＲ_２）、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ_２、－Ｃ（Ｏ）Ｎ（Ｒ）ＯＲ、－ＯＣ（Ｏ）Ｒ、－ＯＣ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、－Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、－Ｎ（Ｒ）Ｃ（Ｏ）ＮＲ_２、－Ｎ（Ｒ）Ｓ（Ｏ）_２Ｒ、－ＯＰ（Ｏ）Ｒ_２、－ＯＰ（Ｏ）（ＯＲ）_２、－ＯＰ（Ｏ）（ＯＲ）ＮＲ_２、－ＯＰ（Ｏ）（ＮＲ_２）_２、および－ＳｉＲ_３から選択され；
各Ｒ^４は独立して、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式環、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択される、必要に応じて置換された基から選択され；

は、単結合または二重結合であり；
ｍは、０、１、２、３または４であり；
ｎは、０、１、２、３または４であり；そして
ｏは、０、１、または２である。 In certain embodiments, the present invention provides a method for the treatment of cancer, wherein the LBM is a CRBN E3 ubiquitin ligase binding moiety, whereby the LBM has formula I-qqq:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and as described in embodiments herein, and wherein:
Each ^X1 is independently

and
^X2 and ^X3 are independently _-CH2- , -C(O)-, -C(S)-, or
and
^Z1 and ^Z2 are independently a carbon atom or a nitrogen atom;
Ring A is a fused ring selected from a 4- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from benzo, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -S-, -C(O)-, -C(S)-, -CR ₂ -, -CRF-, -CF ₂ -, -NR-, or -S(O) ₂ -;
Each R ¹ is independently hydrogen, R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -CF ₂ R, -CR ₂ F, -CF ₃ , -CR ₂ (OR), -CR ₂ (NR ₂ ), -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -C(S)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ , -Si(OR)R ₂ , and -SiR ₃ ; or two R ¹ groups optionally taken together form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Each R is independently selected from hydrogen or an optionally selected group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
^R2 is
or hydrogen;
Ring B is phenyl, a 4-10 membered saturated or partially unsaturated, monocyclic or bicyclic, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Ring B is optionally further substituted with 1-2 oxo groups;
Each R ³ is independently hydrogen, R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -CF ₂ R, -CF ₃ , -CR ₂ (OR), -CR ₂ (NR ₂ ), -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -OP(O)R ₂ , -OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ , and —SiR ₃ ;
each R ⁴ is independently selected from an optionally substituted group selected from a C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

is a single bond or a double bond;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4; and o is 0, 1, or 2.

である。 As defined above and described herein, each X ¹ independently represents a covalent bond, —CH ₂ —, —O—, —NR—, —CF ₂ —,

It is.

である。いくつかの実施形態において、Ｘ^１は－Ｃ（Ｏ）－である。いくつかの実施形態において、Ｘ^１は－Ｃ（Ｓ）－である。いくつかの実施形態において、Ｘ^１は
である。 In some embodiments, X ¹ is a covalent bond. In some embodiments, X ¹ is -CH ₂ -. In some embodiments, X ¹ is -O-. In some embodiments, X ¹ is -NR-. In some embodiments, X ¹ is -CF ₂ -. In some embodiments, X ¹ is

In some embodiments, X ¹ is -C(O)-. In some embodiments, X ¹ is -C(S)-. In some embodiments, X ¹ is
It is.

In certain embodiments, X ¹ is selected from those shown in the compounds of Table 1.

As defined above and described herein, X ² and X ³ are independently -CH ₂ -, -C(O)-, -C(S)-, or
It is.

In some embodiments, X ² and X ³ are independently -CH ₂ -. In some embodiments, X ² and X ³ are independently -C(O)-. In some embodiments, X ² and X ³ are independently -C(S)-. In some embodiments, X ² and X ³ are independently
It is.

In certain embodiments, X ² and X ³ are independently selected from those shown in the compounds of Table 1.

である。 As defined above and described herein, X ⁴ is a covalent bond, —CH ₂ —, —CR ₂ —, —O—, —NR—, —CF ₂ —,

It is.

As defined above and described herein, Z ¹ and Z ² are independently a carbon atom or a nitrogen atom.

In some embodiments, Z ¹ and Z ² are independently a carbon atom. In some embodiments, Z ¹ and Z ² are independently

In certain embodiments, Z ¹ and Z ² are independently selected from those shown in the compounds of Table 1.

As defined above and described herein, Ring A is a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ring A is benzo. In some embodiments, ring A is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, ring A is selected from those shown in the compounds of Table 1.

As defined above and described herein, L ¹ is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -S-, -C(O)-, -C(S)-, -CR ₂ -, -CRF-, -CF ₂ -, -NR-, or -S(O) ₂ -.

In some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, where one to two methylene units of the chain are independently optionally replaced with -O-, -S-, -C(O)-, -C(S)-, -CR ₂ -, -CRF-, -CF ₂ -, -NR-, or -S(O) ₂ -.

In some embodiments, L ¹ is —C(O)—.

In certain embodiments, L ¹ is selected from those shown in the compounds of Table 1.

As defined above and described herein, each R ¹ is independently hydrogen, R ⁴ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —CF ₂ R, —CF ₃ , —CR ₂ (OR), —CR ₂ (NR ₂ ), —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —C(S)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , —N(R)S(O) ₂ R, —OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ , -Si(OR)R ₂ , and -SiR ₃ , or two R ¹ groups optionally taken together form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is R ^4. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -NO _2. In some embodiments, R ¹ is -OR. In some embodiments, R ¹ is -SR. In some embodiments, R ¹ is -NR _2. In some embodiments, R 1 is -S(O) ₂ R. In some embodiments, R ¹ is -S(O) ₂ NR _2. In some embodiments, R ¹ is -S(O)R. In some embodiments, R ¹ is -CF ₂ R. In some embodiments, R ¹ is -CF _3. In some embodiments, R ¹ is -CR ₂ (OR). In some embodiments, R ¹ is -CR ₂ (NR ₂ ) ^{. In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C} (O)OR. In some embodiments, R ¹ is -C(O)NR _2. In some embodiments, R ¹ is -C(O)N(R)OR. In some embodiments, R ¹ is -OC(O)R. In some embodiments, R ¹ is -OC(O)NR _2. In some embodiments, R ¹ is -C(S)NR _2. In some embodiments, R 1 is -N(R)C(O)OR. In some embodiments, R ¹ is -N(R)C(O)R. In some embodiments, R ¹ is -N(R)C(O)NR _2. In some embodiments, R ¹ is -N(R)S(O) ₂ R. In some embodiments, R ¹ is -OP(O)R _2. In some embodiments, R ¹ is -OP(O)(OR) _2. In some embodiments, R ¹ is -OP(O)(OR)NR ² _. In some embodiments, R ¹ is -OP(O)(NR ₂ ) _2. In some embodiments, R ¹ is -Si(OR)R _2. In some embodiments, R ¹ is -SiR _3. In some embodiments, two R ¹ groups optionally join together to form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, each R ¹ is independently selected from those shown in the compounds of Table 1.

As defined above and described herein, each R is independently selected from hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally join with the atoms between them to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C _1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen, optionally taken together with atoms between them, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As defined above and described herein, ^R2 is
or hydrogen.

In some embodiments, ^R2 is
In some embodiments, ^R2 is hydrogen.

In certain embodiments, R ² is selected from those depicted in the compounds of Table 1.

As defined above and described herein, Ring B is a phenyl, a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Ring B is further optionally substituted with 1 to 2 oxo groups.

In some embodiments, Ring B is phenyl. In some embodiments, Ring B is a 4-10 membered, saturated or partially unsaturated, monocyclic or bicyclic, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is further optionally substituted with 1-2 oxo groups.

In certain embodiments, ring B is selected from those compounds shown in Table 1.

As defined above and described herein, each R ³ is independently hydrogen, R ⁴ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —CF ₂ R, —CF ₃ , —CR 2 (OR), —CR ₂ (NR ₂ ), _—C (O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR _{2 ,} —N(R)S(O) ₂ R, —OP(O)R _{2 .} , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ , and —SiR ₃ .

In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is R ^4. In some embodiments, R ³ is halogen. In some embodiments, R ³ is -CN. In some embodiments, R ³ is -NO _2. In some embodiments, R ³ is -OR. In some embodiments, R ³ is -SR. In some embodiments, R ³ is -NR _2. In some embodiments, R 3 is -S(O) ₂ R. In some embodiments, R ³ is -S(O) ₂ NR _2. In some embodiments, R ³ is -S(O)R. In some embodiments, R ³ is -CF ₂ R. In some embodiments, R ³ is -CF _3. In some embodiments, R ³ is -CR ₂ (OR). In some embodiments, R ³ is -CR ₂ (NR ₂ ) ^{. In some embodiments, R 3 is -C(O)R. In some embodiments, R 3 is -C} (O)OR. In some embodiments, R ³ is -C(O)NR _2. In some embodiments, R ³ is -C(O)N(R)OR. In some embodiments, R ³ is -OC(O)R. In some embodiments, R ³ is -OC(O)NR _2. In some embodiments, R ³ is -N(R)C(O)OR. In some embodiments, R ³ is -N(R)C(O)R. In some embodiments, R ³ is -N(R)C(O)NR _2. In some embodiments, R ³ is -N(R)S(O) ₂ R. In some embodiments, R ³ is -OP(O)R _2. In some embodiments, R ³ is -OP(O)(OR) _2. In some embodiments, R ³ is -OP(O)(OR)NR _2. In some embodiments, R ³ is -OP(O)(NR ₂ ) ₂ . In some embodiments, ^R3 is _--SiR3 .

In certain embodiments, R ³ is selected from those depicted in the compounds of Table 1.

As defined above and described herein, each ^R4 is independently an optionally substituted group selected from _C1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ⁴ is an optionally substituted C _1-6 aliphatic. In some embodiments, R ⁴ is an optionally substituted phenyl. In some embodiments, R ⁴ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁴ is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, R ⁴ is selected from those depicted in the compounds of Table 1.

As defined above and described in embodiments herein,
is a single bond or a double bond.

In some embodiments,
is a single bond. In some embodiments,
is a double bond.

In certain embodiments,
is selected from those shown in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3, or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

In certain embodiments, m is selected from the compounds shown in Table 1.

As defined above and described herein, n is 0, 1, 2, 3, or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In certain embodiments, n is selected from those compounds shown in Table 1.

As defined above and described herein, o is 0, 1, or 2.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 2.

In certain embodiments, o is selected from the compounds shown in Table 1.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｑｑｑの化合物を提供し、ここでＣＢＭ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、およびｍの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds of formula I-qqq-1: wherein ring A is benzo, o is 1, X ¹ is —CH ₂ —, X ² and X ³ are —C(O)—, and Z ¹ and Z ² are carbon atoms, as shown.

or a pharma- ceutically acceptable salt thereof, wherein each of CBM, L, L ¹ , R ¹ , R ² , and m, both alone and in combination, is as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を提供している、式Ｉ－ｑｑｑの化合物を提供し、ここでＣＢＭ、Ｌ、Ｌ^１、Ｒ^１、Ｒ^２、およびｍの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides compounds of formula I-qqq-12, wherein ring A is benzo, o is 1, X ¹ , X ² and X ³ are -C(O)-, and Z ¹ and Z ² are carbon atoms, as shown:

or a pharma- ceutically acceptable salt thereof, wherein each of CBM, L, L ¹ , R ¹ , R ² , and m, both alone and in combination, is as defined above and as described in embodiments herein.

In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
In some embodiments, the LBM is
It is.

In some embodiments, the LBM is selected from those in Table 1 below.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ａ、Ｙ、およびＺの各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１９／１６５２２９に記載および定義されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is an RPN13 binding moiety, whereby the compound has the formula I-rrr:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in the embodiments herein, and each of the variables A, Y, and Z are as described and defined in WO 2019/165229, each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In certain embodiments, the invention relates to a method for the preparation of a Ubr1 binding moiety, wherein the LBM is a Ubr1 binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem. 2019, doi:10.1074/jbc.AC119.010790, each of which is incorporated by reference herein in its entirety, whereby the LBM has the formula I-sss-1 or I-sss-2:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｙ、Ａ^１、およびＡ^３の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０１９／２３６４８３に記載および定義されるとおりである。 In certain embodiments, the present invention provides a CRBN E3 ubiquitin ligase binding moiety, whereby the LBM is a CRBN E3 ubiquitin ligase binding moiety, represented by formula I-uuu-1, I-uuu-2, I-uuu-3, or I-uuu-4:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in the embodiments herein, and each of the variables Y, ^A1 , and ^A3 are as described and defined in WO 2019/236483, each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In a particular embodiment, the present invention relates to a method for the preparation of a polypeptide comprising the LBM of formula I-vvv:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In certain embodiments, the present invention relates to a method for the treatment of cancer, wherein the LBM is a KEAP1 binding moiety as described in Lu et al., Euro. J. Med. Chem., 2018, 146:251-9, whereby the LBM has the formula I-:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM, both alone and in combination, are as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、上で定義され、そして本明細書中の実施形態に記載されるとおりであり、そして可変物Ｒ、Ｒ_１、Ｒ_５、およびＲ_８の各々は、その各々の全体が本明細書中に参考として援用されるＷＯ ２０２０／０１８７８８に記載および定義されるとおりである。 In certain embodiments, the present invention provides a compound according to the invention, wherein the LBM is a KEAP1-NRF2 binding moiety, whereby the compound has formula I-xxx or I-xxx-2:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and in embodiments herein, and each of the variables R, _R1 , _R5 , and _R8 are as described and defined in WO 2020/018788, each of which is incorporated herein by reference in its entirety.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＬおよびＣＢＭは、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In certain embodiments, the invention relates to a method for the preparation of a KEAP1-NRF2 binding moiety, wherein the LBM is a KEAP1-NRF2 binding moiety as described in Tong et al., "Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone", ChemRxiv 2020, whereby the LBM is represented by formula I-yyy-1 or I-yyy-2:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM, both alone and in combination, are as defined above and as described in embodiments herein.

In some embodiments, the LBM is
In some embodiments, the LBM is
It is.

の化合物またはその薬学的に受容可能な塩を提供し、ここでＬおよびＣＢＭは、上記および本明細書中に記載されるとおりであり、そしてＤＩＭは、ＬＢＭ、リジン模倣物、または水素原子から選択される分解誘導部分である。 Decomposition Inducing Moiety (DIM)
In certain embodiments, the present invention provides a compound of formula I:

or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as described above and herein, and DIM is a decomposition-inducing moiety selected from an LBM, a lysine mimetic, or a hydrogen atom.

In some embodiments, the DIM is an LBM as described above and herein. In some embodiments, the DIM is a lysine mimetic. In some embodiments, the covalent attachment of ubiquitin to the CDK2 protein is achieved by the action of the lysine mimetic. In some embodiments, when a compound of formula I binds to the CDK2 protein, the lysine mimetic moiety undergoes ubiquitination, thereby marking the CDK2 protein for degradation via the ubiquitin-proteasome pathway (UPP).

In some embodiments, the DIM is
In some embodiments, the DIM is
In some embodiments, the DIM is
It is.

In some embodiments, the DIM is selected from those illustrated in Table 2 below.

の化合物またはその薬学的に受容可能な塩としての、式Ｉの化合物を提供し、ここでＣＢＭおよびＬの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound of formula I-aaaa:

or a pharma- ceutically acceptable salt thereof, wherein each of CBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩としての、式Ｉの化合物を提供し、ここでＣＢＭおよびＬの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound of formula I-aaaa-1:

or a pharma- ceutically acceptable salt thereof, wherein each of CBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

の化合物またはその薬学的に受容可能な塩としての、式Ｉの化合物を提供し、ここでＣＢＭおよびＬの各々は、単独でと組み合わせてとの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound of formula I-aaaa-2:

or a pharma- ceutically acceptable salt thereof, wherein each of CBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

In certain embodiments, the present invention relates to a method for treating a pulmonary artery disease in which the DIM is a lysine mimetic.
whereby the compound has formula I-bbbb-1, I-bbbb-2, or I-bbbb-3, respectively:
or a pharma- ceutically acceptable salt thereof, wherein L and CBM are as defined above and described in embodiments herein, and each of the variables ^R1 , ^R4 , ^R5 , A, B, E, Y, Y', Z, Z', and k are as defined and described in U.S. Pat. No. 7,622,496, each of which is incorporated by reference in its entirety herein.

Hydrogen Atom In some embodiments, DIM is a hydrogen atom. In some embodiments, covalent attachment of ubiquitin to the CDK2 protein is achieved by provided compounds in which DIM is a hydrogen atom. In some embodiments, when a compound of formula I binds to the CDK2 protein, the moiety that is hydrogen achieves ubiquitination, thereby marking the CDK2 protein for degradation via the ubiquitin-proteasome pathway (UPP).

In some embodiments, the DIM is selected from those illustrated in Table 2 below.

の化合物またはその薬学的に受容可能な塩を形成している、式Ｉの化合物を提供し、ここでＣＢＭおよびＬの各々は、単独でと組み合わせでの両方で、上で定義され、そして本明細書中の実施形態に記載されるとおりである。 In some embodiments, the present invention provides a compound according to the present invention, wherein DIM is a hydrogen atom, thereby providing a compound according to formula I-cccc:

or a pharma- ceutically acceptable salt thereof, wherein each of CBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

Linker (L)
As defined above and described herein, L is a divalent moiety that links the CBM to the LBM or the CBM to the DIM.

In some embodiments, L is a bivalent moiety that links the CBM to the LBM. In some embodiments, L is a bivalent moiety that links the CBM to the DIM. In some embodiments, L is a bivalent moiety that links the CBM to the lysine mimetic.

により置き換えられており、ここで：
各－Ｃｙ－は独立して、フェニレニル、８員～１０員の二環式アリーレニル、４員～７員の飽和もしくは部分不飽和のカルボシクリレニル、４員～１１員の飽和もしくは部分不飽和のスピロカルボシクリレニル、８員～１０員の二環式の飽和もしくは部分不飽和のカルボシクリレニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和もしくは部分不飽和のヘテロシクリレニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～１１員の飽和もしくは部分不飽和のスピロヘテロシクリレニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する８員～１０員の二環式の飽和もしくは部分不飽和のヘテロシクリレニル、窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリーレニル、ならびに窒素、酸素、および硫黄から独立して選択される１個～５個のヘテロ原子を有する８員～１０員の二環式のヘテロアリーレニルから選択される、必要に応じて置換された二価の環であり、
各Ｒは独立して、水素、または必要に応じて置換された基であり、この必要に応じて置換された基は、Ｃ_１～６脂肪族、フェニル、窒素、酸素、および硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～７員の飽和または部分不飽和の複素環式、ならびに窒素、酸素、および硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員のヘテロアリール環から選択されるか、あるいは：
同じ窒素上の２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、この窒素に加えて、窒素、酸素、および硫黄から独立して選択される０個～３個のヘテロ原子を有する４員～７員の飽和、部分不飽和、またはヘテロアリールの環を形成し、そして；
ｒは、０、１、２、３、４、５、６、７、８、９、または１０である。 In some embodiments, L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C _1-50 hydrocarbon chain, where the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

has been replaced by:
Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from saturated or partially unsaturated spiroheterocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, each -Cy- is independently an optionally substituted bivalent phenylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic arylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 7-membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
In some embodiments, -Cy- is
It is.

In some embodiments, -Cy- is optionally substituted with one or more fluoro atoms.

In some embodiments, -Cy- is selected from those depicted in Table 2 below.

In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.

In some embodiments, r is selected from those depicted in Table 2 below.

In some embodiments, L is -NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NR-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-NR-(C _{1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10 aliphatic} )-NR-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-NR-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10} aliphatic)-NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NR-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-NR-. In some embodiments, L is -Cy-(C 1-10 aliphatic} )-NR-Cy-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-Cy-NR-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-NR-(C _1-10 aliphatic)-. _{In some embodiments, L is -Cy-(C 1-10 aliphatic} )-NR-Cy-.

In some embodiments, L is -CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-CONR-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-CONR-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-CONR-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-CONR-. In some embodiments, L is -Cy-(C 1-10} aliphatic)-CONR-Cy-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-CONR-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-CONR-(C _1-10 aliphatic)-.

In some embodiments, L is -NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NRCO-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-NRCO-(C _{1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10 aliphatic} )-NRCO-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NRCO-(C 1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NRCO-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-NRCO-. In some embodiments, L is -Cy-(C 1-10 aliphatic} )-NRCO-Cy-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-Cy-NRCO-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NRCO-Cy ...(C _1-10 aliphatic)-.

In some embodiments, L is -O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-O-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-O-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-O-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-O-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-O-. In some embodiments, L is -Cy-(C 1-10 aliphatic} )-O-Cy-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-Cy-O-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-O-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-Cy-(C _1-10 aliphatic)-.

In some embodiments, L is -Cy-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-. In some embodiments, L is -Cy-(C 1-10 aliphatic} )-Cy-(C _{1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-Cy-(C 1-10} aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-Cy-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-.

In some embodiments, L is -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NR-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-NR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH _{2 ) 1-10 -NR-. In some embodiments, L is -Cy-(CH 2 ) 1-10} -NR-(CH _{2 ) 1-10} -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -NR-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NR-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NR-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NR-Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -CONR-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-CONR-(CH ₂ ) 1-10 -. In some embodiments, L is -Cy-(CH _{2 ) 1-10 -CONR-. In some embodiments, L is -Cy-(CH 2 ) 1-10 -CONR-} (CH _{2 ) 1-10} -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) 1-10 -Cy-(CH ₂ ) _1-10 -CONR-. In some embodiments, L is -(CH ₂ ) _{1-10 -Cy-} (CH ₂ ) _1-10 -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-CONR-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -CONR-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -CONR-Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NRCO-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH _{2 ) 1-10 -NRCO-. In some embodiments, L is -Cy-(CH 2 ) 1-10} -NRCO-(CH _{2 ) 1-10} -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) 1-10 -Cy-(CH ₂ ) _1-10 -NRCO-. In some embodiments, L is -(CH ₂ ) _{1-10 -Cy-} (CH ₂ ) _1-10 -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NRCO-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NRCO-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NRCO-Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -O-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-O-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH 2 ) 1-10 -O-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH _{2 ) 1-10 -Cy} -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -O-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -O-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-O-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -O-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-O-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -O-Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is -Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-(CH ₂ ) 1-10 -Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -Cy- _. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is
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It is.

In some embodiments, L is
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It is.

In some embodiments, L is also selected from those illustrated in Table B below.

In some embodiments, L is selected from those depicted in Table 1 below.

のいずれかであり得る。 The attachment points of L to the CBM and DIM can be, for example and without limitation,
If it is,

It can be either of the following.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
is selected from those in which:

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof include those in which the CBM is:
and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

In some embodiments, the present invention provides a compound having a CBM as described and disclosed herein, an LBM as described in Table A above, and a linker as described in Table B above, or a pharma- ceutically acceptable salt thereof.

Exemplary compounds of the present invention are set forth in Table 1 below.

In some embodiments, the present invention provides a compound described in Table 2 above, or a pharma- ceutically acceptable salt thereof.

4. General Methods of Providing the Compounds The compounds of the present invention may generally be prepared or isolated by synthetic and/or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods detailed in the Examples herein.

In the following schemes, where a particular protecting group, leaving group, or transformation condition is illustrated, one of skill in the art will understand that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformation conditions are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, ^5th Edition, John Wiley & Sons, 2001; Comprehensive Organic Transformations, R. C. Larock, ^2nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, ^3rd edition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety.

As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting group, hydroxyl protecting group, and the like. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, ^3rd edition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety. Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxy alkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalates (trimethylacetyl), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoates, 2,4,6-trimethylbenzoates, carbonates (such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl). Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, ^3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimido, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

In the schemes below, where provided compounds are formed that have a reactive moiety (e.g., amine, alcohol, etc.), although not shown, it is generally recognized and well known by those skilled in the art that the reactivity of the reactive moiety may be masked by using an appropriate protecting group, which may then be removed in situ or during a separate synthetic step.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 1 below:
Scheme 1: Synthesis of compounds of formula I

は、それぞれ、ＣＢＭとＡ－１の末端アミノ基との間のリンカーの部分、またはＤＩＭとＡ－２の末端カルボキシル基との間のリンカーの部分を表す。アミド結合は、当該分野において公知であるカップリング試薬（例えば、ＤＣＣ、ＤＩＣ、ＥＤＣ、ＨＡＴＵ、ＨＢＴＵ、ＨＣＴＵ、ＰｙＡＯＰ、ＰｙＢＯＰ、ＰｙＢｒＯＰ、ＢＯＰ、ＢＯＰ－Ｃｌ、ＤＥＰＢＴ、Ｔ３Ｐ、ＴＡＴＵ、ＴＢＴＵ、ＴＮＴＵ、ＴＯＴＵ、ＴＰＴＵ、ＴＳＴＵ、またはＴＤＢＴＵであるがこれらに限定されない）を使用して形成され得る。 As illustrated in Scheme 1 above, amine A-1 is coupled to acid A-2 using a coupling agent in the presence of a base (e.g., DIPEA) in a solvent (e.g., DMF) to form a compound of formula I having a linker that includes an amide bond.

represent the portion of the linker between CBM and the terminal amino group of A-1, or the portion of the linker between DIM and the terminal carboxyl group of A-2, respectively. The amide bond can be formed using coupling reagents known in the art, such as, but not limited to, DCC, DIC, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generally prepared according to Scheme 2 below:
Scheme 2: Synthesis of compounds of formula I

は、それぞれ、ＣＢＭとＡ－３の末端カルボキシル基との間のリンカーの部分、またはＤＩＭとＡ－４の末端アミノ基との間のリンカーの部分を表す。アミド結合は、当該分野において公知であるカップリング試薬（例えば、ＤＣＣ、ＤＩＣ、ＥＤＣ、ＨＡＴＵ、ＨＢＴＵ、ＨＣＴＵ、ＰｙＡＯＰ、ＰｙＢＯＰ、ＰｙＢｒＯＰ、ＢＯＰ、ＢＯＰ－Ｃｌ、ＤＥＰＢＴ、Ｔ３Ｐ、ＴＡＴＵ、ＴＢＴＵ、ＴＮＴＵ、ＴＯＴＵ、ＴＰＴＵ、ＴＳＴＵ、またはＴＤＢＴＵであるがこれらに限定されない）を使用して形成され得る。 As illustrated in Scheme 2 above, acid A-3 is coupled to amine A-4 using a coupling agent in a solvent (e.g., DMF) in the presence of a base (e.g., DIPEA) to form a compound of formula I having a linker that includes an amide bond.

represent the portion of the linker between CBM and the terminal carboxyl group of A-3, or the portion of the linker between DIM and the terminal amino group of A-4, respectively. The amide bond can be formed using coupling reagents known in the art, such as, but not limited to, DCC, DIC, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 3 below:
Scheme 3: Synthesis of compounds of formula I

は、それぞれ、ＣＢＭとＡ－５の末端アミノ基との間のリンカーの部分を表す。 As depicted in Scheme 3 above, S _N Ar displacement of fluoride A-6 with amine A-5 is carried out in a solvent (e.g., DMF) in the presence of a base (e.g., DIPEA) to form compounds of formula I having a linker containing a secondary amine.

each represents the portion of the linker between the CBM and the terminal amino group of A-5.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 4 below:
Scheme 4: Synthesis of compounds of formula I

は、それぞれ、ＤＩＭとＡ－８の末端アミノ基との間のリンカーの部分を表す。
スキーム５：式Ｉの化合物の合成

As illustrated in Scheme 4 above, S _N Ar displacement of fluoride A-7 with amine A-8 is carried out in a solvent such as DMF in the presence of a base such as DIPEA to form compounds of formula I having a linker containing a secondary amine.

each represents the portion of the linker between DIM and the terminal amino group of A-8.
Scheme 5: Synthesis of compounds of formula I

は、それぞれ、ＤＩＭとＡ－８の末端アミノ基との間のリンカーの部分を表す。 As illustrated in Scheme 7 above, reductive amination of fluoride A-7 with amine A-8 is carried out in the presence of a reducing agent (e.g., NaHB(OAc) ₃ ) and a base (e.g., KOAc) in a solvent (e.g., DMF/THF) to form compounds of formula I having a linker containing a secondary amine.

each represents the portion of the linker between DIM and the terminal amino group of A-8.

Those skilled in the art will recognize that various functional groups present in the compounds of the present invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles, may be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration and hydration. March's Advanced Organic Chemistry, ^5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing the compounds of the present invention are described in the following examples.

5. Use, Formulation and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharma- ceutically acceptable derivative thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to measurably degrade and/or inhibit a CDK protein or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably degrade and/or inhibit a CDK protein or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

"Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of this invention or an inhibitory or degradative active metabolite or residue thereof.

As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of a CDK protein or a mutant thereof.

As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degrader of the CDK protein or a variant thereof.

The compositions of the invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated form, are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, commonly used in the formulation of pharma- ceutical acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharma- ceutical acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

The pharma- ceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added, if desired.

Alternatively, the pharma- ceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

The pharma- ceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. A topical transdermal patch may also be used.

For topical application, the pharma- ceutically acceptable compositions provided may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharma- ceutically acceptable compositions provided may be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharma- ceutically acceptable compositions provided may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or, preferably, as solutions in isotonic, pH-adjusted, sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharma-ceutically acceptable compositions may be formulated in an ointment, such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharma- ceutically acceptable compositions of the invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions of the invention are administered without food. In other embodiments, the pharma- ceutically acceptable compositions of the invention are administered with food.

The amount of the compounds of the present invention that may be combined with carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage of between 0.01-100 mg of compound per kg of body weight per day can be administered to a patient receiving these compositions.

It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also vary depending on the particular compound in the composition.

Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading and/or inhibiting the kinase activity of one or more enzymes.

As used herein, the terms "CDK1-mediated," "CDK2-mediated," "CDK4-mediated," "CDK6-mediated," "CDK7-mediated," "CDK8-mediated," and/or "CDK9-mediated" disorders, diseases, and/or conditions, as used herein, refer to any disease or other deleterious condition in which one or more of CDK1, CDK2, CDK4, CDK6, CDK7, CDK8, CDK9, or variants thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which one or more of CDK1, CDK2, CDK4, CDK6, CDK7, CDK8, and/or CDK9, or variants thereof, are known to play a role. In some embodiments, the term "mediated by CDK2" also includes treating or reducing the severity of one or more diseases in which CCNE (e.g., CCNE1) or more are known to play a role.

The compounds of the present disclosure can degrade CDK2 or CDK2 and CCNE1, and are therefore useful for treating diseases whose underlying pathology is mediated, in whole or in part, by CDK2. Such diseases include cancer and other diseases with proliferation disorders. In some embodiments, the present disclosure provides in vivo treatment of an individual or patient using a provided compound or a pharma- ceutically acceptable salt thereof such that the growth of a cancerous tumor is inhibited. The provided compound or a pharma- ceutically acceptable salt thereof can be used to inhibit the growth of a cancerous tumor having an abnormality that activates CDK2 activity. These include, but are not limited to, diseases (e.g., cancer) characterized by the amplification or overexpression of CCNE1, such as ovarian, uterine and breast cancer, and diseases (e.g., cancer) characterized by the inactivation of p27, such as breast cancer and melanoma. Thus, in some embodiments of these methods, the patient has previously been determined to have an amplification of the CCNE1 gene and/or an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. Alternatively, the provided compounds or pharma- ceutically acceptable salts thereof may be used in combination with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a provided compound or a pharma- ceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells having CCNE1 amplification and overexpression in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of a provided compound or a pharma- ceutically acceptable salt thereof.

In some embodiments, provided herein is a method of inhibiting CDK2, the method comprising contacting CDK2 with a provided compound, or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of inhibiting CDK2 in a patient, the method comprising administering to the patient a provided compound, or a pharma- ceutically acceptable salt thereof.

In some embodiments, provided herein is a method of inhibiting CDK2 and CCNE1, the method comprising contacting CDK2 and CCNE1 with a provided compound or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of inhibiting CDK2 and CCNE1 in a patient, the method comprising administering to the patient a provided compound or a pharma- ceutically acceptable salt thereof.

In some embodiments, provided herein is a method of degrading CDK2, the method comprising contacting CDK2 with a provided compound or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 in a patient, the method comprising administering to the patient a provided compound or a pharma- ceutically acceptable salt thereof.

In some embodiments, provided herein is a method of degrading CDK2 and inhibiting CCNE1, the method comprising contacting CDK2 and CCNE1 with a provided compound, or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 and inhibiting CCNE1 in a patient, the method comprising administering to the patient a provided compound, or a pharma-ceutically acceptable salt thereof.

In some embodiments, provided herein is a method of degrading CDK2 and CCNE1, the method comprising contacting CDK2 and CCNE1 with a provided compound or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 and CCNE1 in a patient, the method comprising administering to the patient a provided compound or a pharma- ceutically acceptable salt thereof.

In some embodiments, provided herein is a method for treating cancer. The method includes administering to a patient in need thereof a therapeutically effective amount of a provided compound or a pharma- ceutically acceptable salt thereof. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian or breast cancer characterized by amplification or overexpression of CCNE1.

In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with CDK2 is associated with amplification of the CCNE1 gene and/or overexpression of CCNE1.

In some embodiments, the CDK2-associated disease or disorder is N-myc-amplified neuroblastoma cells (see Molenaar et al., Proc. Natl. Acad. Sci. USA, 2009, 106(31):12968-12973), K-Ras-mutated lung cancer (see Hu, S., et al., Mol. Cancer Ther., 2015, 14(11):2576-85), and cancer with FBW7 mutation and CCNE1 overexpression (see Takada et al., Cancer Res., 2017, 77(18):4881-4893).

In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, invasive breast carcinoma, uterine carcinoma, serous ovarian cystadenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, invasive breast carcinoma, uterine carcinoma, serous ovarian cystadenocarcinoma, or gastric adenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

In some embodiments, the disease or disorder associated with CDK2 is cancer.

In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian or breast cancer characterized by amplification or overexpression of CCNE1.

In some embodiments, the breast cancer is chemotherapy- or radiation-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4/6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

Examples of cancers that can be treated using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, cancer of the fallopian tubes, cancer of the endometrium, endometrial cancer, cancer of the cervix, cancer of the vagina, cancer of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, acute myeloid leukemia, chronic myeloid leukemia, The cancers include, but are not limited to, chronic or acute leukemias, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or urethra, cancer of the renal pelvis, central nervous system (CNS) neoplasms, primary CNS lymphomas, tumor angiogenesis, tumors of the spinal axis, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinomas, squamous cell carcinomas, T-cell lymphomas, environmentally induced cancers, including those induced by asbestos, and combinations of these cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate cancer), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder), and cancers with high microsatellite instability (MSI ^high ). Additionally, the present disclosure includes refractory or recurrent malignancies.

In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of these cancers.

In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, oral cancer, mouth cancer, throat cancer, pharyngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular adenocarcinoma, urethral cancer, and ureteral cancer.

In some embodiments, the compounds of the present disclosure may be used to treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), cancer of the stomach (carcinoma, lymphoma, leiomyosarcoma), cancer of the pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), cancer of the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), cancer of the large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include kidney (adenocarcinoma, Wilms' tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochronfloma (chondroosseous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

Exemplary gynecologic cancers include cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and cancer (carcinoma) of the fallopian tubes.

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

It is believed that the provided compounds or pharma- ceutically acceptable salts thereof may have a satisfactory pharmacological profile and promising biopharmaceutical properties, e.g., toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. It is understood that determining appropriate biopharmaceutical properties, e.g., cytotoxicity in cells, or inhibition of specific targets or channels to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and/or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

The terms "individual" or "patient" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

The phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response desired by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases described herein, e.g., for preventing or reducing the risk of developing a disease, condition or disorder in an individual who may have a predisposition to the disease, condition or disorder, but who has not experienced or displayed the pathology or symptoms of the disease.

Co-administration with One or More Other Therapeutic Agents Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition can also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

In some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, e.g., those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent(s) acts synergistically.

The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

The compounds of the invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of a fixed combination or administration of the compounds of the invention and one or more other therapeutic compounds given in a staggered or independent manner, or in the form of combined administration of a fixed combination with one or more other therapeutic compounds. The compounds of the invention can be administered other than or in addition to chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, in particular for tumor treatment. As described above, long-term treatment is possible, as well as adjuvant treatment, in the context of other treatment strategies. Other possible treatments are treatments to maintain the patient's condition after tumor regression, or even chemopreventive treatments, for example in patients at risk.

The one or more other therapeutic agents may be administered separately from the compounds or compositions of the invention as part of a multiple dose regimen. Alternatively, the one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. When administered as a multiple dose regimen, the one or more other therapeutic agents and the compounds or compositions of the invention may be administered simultaneously, sequentially, or within a period of time from each other, for example, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 18 hours, 20 hours, 21 hours, 22 hours, 23 hours, or within 24 hours of each other. In some embodiments, the one or more other therapeutic agents and the compounds or compositions of the invention are administered as a multiple dose regimen more than 24 hours apart.

As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the invention. For example, a compound of the invention may be administered with one or more other therapeutic agents simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the invention provides a single unit dosage form containing a compound of the invention, one or more other therapeutic agents, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

The amount of the compounds of the present invention and one or more other therapeutic agents (in compositions containing additional therapeutic agents as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of the present invention should be formulated so that 0.01 to 100 mg/kg body weight/day of the compounds of the present invention can be administered.

In compositions containing one or more other therapeutic agents, the one or more other therapeutic agents and the compound of the present invention may act synergistically. Thus, the amount of the one or more other therapeutic agents in such compositions may be less than would be required in a monotherapy utilizing only that therapeutic agent. In such compositions, dosages of 0.01 to 1,000 μg/kg body weight/day of the one or more other therapeutic agents may be administered.

The amount of one or more other therapeutic agents present in the compositions of this invention is equal to or less than the amount normally administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of one or more other therapeutic agents in the compositions of this disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the only therapeutically active agent. In some embodiments, the one or more other therapeutic agents are administered at a dosage of 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount that the agent is normally administered. As used herein, the phrase "normally administered" refers to the amount of the FDA approved therapeutic agent provided for administration according to the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharma- ceutically acceptable composition that includes a kinase inhibitor. An implantable device coated with the compounds of this invention is another embodiment of the invention.

Exemplary Other Therapeutic Agents In some embodiments, the one or more other therapeutic agents is a poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, the one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

In some embodiments, the one or more other therapeutic agents are CDK inhibitors, such as CDK4/CDK6 inhibitors. In some embodiments, the CDK 4/6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

In some embodiments, the one or more other therapeutic agents is a phosphatidylinositol 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpesilib (BYL719, Novartis); taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

In some embodiments, the one or more other therapeutic agents are platinum-based therapeutic agents, also referred to as platins. Platins cause cross-linking of DNA such that they inhibit DNA repair and/or DNA synthesis, primarily in rapidly reproducing cells such as cancer cells. In some embodiments, the platinum-based therapeutic agent is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also Teva; Pfizer); oxaliplatin (ELOXITIN®, Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

In some embodiments, the one or more other therapeutic agents are taxane compounds that cause the disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors, i.e., therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylator, YONDELIS®, Janssen Oncology); mechlorethamine (an alkylator, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug of the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), TEMODAR®, Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analogue of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate (a cephalotaxine ester) (a protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EUSA Pharma); eribulin mesylate (eribulin mesylate) (microtubule inhibitor, tubulin-based antimitotic drug, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic drug, JEVTANA®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, thought to form intrastrand DNA crosslinks, TREANDA®, Cephalon/Teva); ixabepilone (semisynthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic drug, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolic inhibitor, ARRANON®, Novartis); chlorafabine (prodrug of an oligonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology).

In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include bevacizumab (Avastin®, Genentech/Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as a VEGF capture agent (Zaltrap®; Regeneron/Sanofi). VEGFR inhibitors (such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai)); Raf inhibitors (sorafenib (Nexavar®, Bayer); AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Nova rtis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targets activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Arunbrig®, Ariad c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®, Excelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfiz er); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinase inhibitors (such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen)); and Flt3 receptor inhibitors (such as midostaurin (Rydapt®, Novartis)).

Other kinase inhibitors and VEGF-R antagonists in development and that can be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang These include: ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/Takeda).

In some embodiments, the one or more other therapeutic agents are mTOR inhibitors, which inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).

In some embodiments, the one or more other therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).

In some embodiments, the one or more other therapeutic agents are growth factor antagonists, such as platelet-derived growth factor (PDGF) or antagonists of epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targets activated EGFR, Tagrisso®, AstraZeneca).

In some embodiments, the one or more other therapeutic agents is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

In some embodiments, the one or more other therapeutic agents are antagonists of the hedgehog pathway. Approved hedgehog pathway inhibitors that may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both of which are for the treatment of basal cell carcinoma.

In some embodiments, the one or more other therapeutic agents are folate inhibitors. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, the one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors currently under investigation that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

In some embodiments, the one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors currently under investigation that can be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, the one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors currently under investigation that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), currently under investigation in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

In some embodiments, the one or more other therapeutic agents are glutaminase inhibitors. Glutaminase inhibitors currently under investigation that can be used in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors currently under investigation that can be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, the one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins undergoing clinical trials and that can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, the one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas/Medivation). Approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor/Ortho); approved antagonists of the gonadotropin-releasing hormone (GnRH) receptor (degalarix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

In some embodiments, the one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and inhibits the binding of RANKL to its receptor RANK, which is found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells and mediates bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, the one or more other therapeutic agents are inhibitors of the interaction between MDMX and MDM2, two major p53 inhibitory proteins. Inhibitors of p53 inhibitory proteins currently under investigation that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that binds equivalently to MDMX and MDM2 and disrupts their interaction with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, progressive myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, the one or more other therapeutic agents are inhibitors of transforming growth factor-beta (TGF-beta or TGFβ). Inhibitors of TGF-beta proteins currently under investigation that can be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody currently being tested in outpatient clinics for the treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), currently under investigation for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a cytotoxic agent as described by Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. For the treatment of solid tumors, one therapeutic compound currently in clinical trials is M7824 (Merck KgaA-formerly MSB0011459X); which is a bispecific anti-PD-L1/TGF-β capture compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF-β "capture agent".

In some embodiments, the one or more other therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody linked to a cytotoxic MMAE (CR011). gpNMB is a protein overexpressed by multiple tumor types that is associated with the ability of cancer cells to metastasize.

In some embodiments, the one or more other therapeutic agents are anti-proliferative compounds, including, but not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that target/reduce protein or lipid kinase activity, and even anti-angiogenic compounds, compounds that target, reduce or inhibit protein or lipid phosphatases, gonadorelin agonists, antiandrogens. Drugs; Methionine aminopeptidase inhibitors; Matrix metalloproteinase inhibitors; Bisphosphonates; Biological response modifiers; Antiproliferative antibodies; Heparanase inhibitors; Inhibitors of Ras oncogenic isoforms; Telomerase inhibitors; Proteasome inhibitors; Compounds used in the treatment of hematological malignancies; Compounds that target Flt-3 and reduce or inhibit its activity; Hsp90 inhibitors (17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, TEMODAL CNF1010, CNF2024, CNF1010 (from Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx); MEK inhibitors (such as ARRY142886 from Array BioPharma, AZd ₆ 244 from AstraZeneca, PD181461 and leucovorin from Pfizer).

The term "aromatase inhibitors", as used herein, relates to compounds that inhibit estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane, and nonsteroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. The combinations of the present invention that include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.

The term "anti-estrogen" as used herein relates to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations of the present invention that include a chemotherapeutic agent that is an anti-estrogen are particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors.

The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological effects of androgens, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogs, 9-nitrocamptothecin and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade names Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron™.

The term "microtubule activator" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubulin polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or sulfate, vincristine or sulfate, and vinorelbine; discodermolide; cochicine and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin R. P™. Vincristine sulfate is commercially available under the trade name Farmistin™.

The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

The term "histone deacetylase inhibitors" or "HDAC inhibitors" refers to compounds which inhibit histone deacetylase and have antiproliferative activity, including but not limited to suberoylanilide hydroxamic acid (SAHA).

The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

The term "compounds which target/reduce the activity of protein kinases or lipid kinases; or compounds which target/reduce the activity of protein phosphatases or lipid phosphatases; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors, or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFRs) (e.g. compounds which target, reduce or inhibit the activity of PDGFRs) b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR) (e.g. compounds which target, reduce or inhibit the activity of IGF-IR, in particular compounds which inhibit the kinase activity of the IGF-I receptor, or antibodies which target the extracellular domain of the IGF-I receptor or its growth factors); d) e) compounds which target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds which target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds which target, reduce or inhibit the activity of the Kit/SCFR receptor tyrosine kinase, e.g. imatinib; h) compounds which target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family (e.g. c-Kit i) compounds which target, reduce or inhibit the activity of the receptor tyrosine kinase family, in particular compounds which inhibit the c-Kit receptor, e.g. imatinib); i) compounds which target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g. BCR-Abl kinase) and mutants (e.g. compounds which target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, e.g. N-phenyl-2-pyrimidine-amine derivatives, e.g. imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825); j) compounds which target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine/threonine kinases, MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC families, and/or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, e.g., midostaurin; further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isochinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors such as imatinib mesylate (Gleevec™) or tyrphostins (e.g. tyrphostin A23/RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957) and adahostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adahostin); l) compounds which target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR ₁ ErbB2, ErbB3, ErbB4, as homodimers or heterodimers) and mutants thereof, for example compounds which target, reduce or inhibit the activity of the epidermal growth factor receptor family are in particular compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, for example the EGF receptor, ErbB2, ErbB3 and ErbB4, or which bind to EGF or EGF related ligands (e.g. CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives); m) targeting, decreasing or inhibiting the activity of the c-Met receptor. compounds that target, reduce or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to compounds that target, reduce or inhibit the kinase activity of the PR T-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparicitinib ... q) compounds that target, decrease or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib).

The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

The term "Bcl-2 inhibitors", as used herein, refers to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

The term "BTK inhibitors" as used herein includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

The term "SYK inhibitors" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, which are incorporated herein by reference in their entireties.

Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, each of which is incorporated herein by reference in its entirety.

Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, each of which is incorporated herein by reference in its entirety.

Additional antiangiogenic compounds include compounds that have another mechanism for their activity, e.g., a mechanism unrelated to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds that target, decrease or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, inhibitors of phosphatase 2A, or inhibitors of CDC25 (e.g., okadaic acid or a derivative thereof).

Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenyl acetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenyl acetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term "bisphosphonates" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to lymphokines or interferons.

The term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) as used herein refers to compounds that target, reduce or inhibit the oncogenic activity of Ras; e.g., "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, reduce or inhibit the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, e.g., telomestatin.

The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduce or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996).

The term "compounds used in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranosylcytosine (ara-c) and busulfan; and ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase.

Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are in particular compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-desmethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), the compounds of the present invention may be used in combination with standard leukemia therapies, in particular in combination with therapies used for the treatment of AML. In particular, the compounds of the present invention may be administered in combination with, for example, farnesyltransferase inhibitors and/or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.

Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, for example, sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US 6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharma- ceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharma- ceutically acceptable salt thereof, particularly the lactate salt. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat or inhibit somatostatin receptors, e.g., octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Ed. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

EDG binders and ribonucleotide reductase inhibitors are also included. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, e.g., FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are, in particular, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

In particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD ₆ 474; SU5416; SU6668; bevacizumab; or anti-VEGF or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI Also included are VEGF compounds, proteins or monoclonal antibodies such as VEGF-specific agonists, such as VEGF-specific agonists (Tregs) and bevacizumab (Avastin™).

Photodynamic therapy, as used herein, refers to treatments that use certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments with compounds such as Visudyne™ and porfimer sodium.

Antiangiostatic steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-alpha-epihydrocortisol, cortexolone, 17alpha-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

The structures of the active compounds identified by code numbers, generic names or trade names can be obtained from the current edition of the standard reference book "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

Exemplary immuno-oncology agents
In some embodiments, the one or more other therapeutic agents are tumor immunotherapeutic agents. As used herein, the term "tumor immunotherapeutic agent" refers to an agent effective to enhance, stimulate, and/or upregulate an immune response in a subject. In some embodiments, administration of a tumor immunotherapeutic agent with a compound of the present invention has a synergistic effect in the treatment of cancer.

The tumor immunotherapy agent can be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological tumor immunotherapy agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

In some embodiments, the tumor immunotherapy agent is (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including costimulatory) signal on a T cell, both of which result in amplification of an antigen-specific T cell response.

Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG. , RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

In some embodiments, the tumor immunotherapy agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

In some embodiments, the combination of the compound of the present invention and an immuno-oncology agent may stimulate a T cell response. In some embodiments, the immuno-oncology agent may be (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor) (e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, C D48, GARP, PD1H, LAIR1, TIM-1, and TIM-4); or (ii) agonists of proteins that stimulate T cell activation (e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H).

In some embodiments, the tumor immunotherapy agent is an antagonist of an inhibitory receptor on an NK cell or an agonist of an activating receptor on an NK cell. In some embodiments, the tumor immunotherapy agent is an antagonist of a KIR, such as lirilumab.

In some embodiments, the tumor immunotherapy agent is an agent that inhibits or depletes macrophages or monocytes, including, but not limited to, a CSF-1R antagonist (e.g., a CSF-1R antagonist antibody, such as RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357)).

In some embodiments, the tumor immunotherapy agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of antitumor T cells, agents that overcome different immune suppressive pathways within the tumor microenvironment (e.g., blocking the engagement of inhibitory receptors (e.g., PD-L1/PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing/preventing T cell energy or exhaustion), and agents that induce innate immune activation and/or inflammation at the tumor site.

In some embodiments, the tumor immunotherapy agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

In some embodiments, the tumor immunoagent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by injection. In some embodiments, the tumor immunoagent is an antibody or antigen-binding portion thereof that specifically binds to the programmed cell death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012/145493). In some embodiments, the tumor immunoagent can be pidilizumab (CT-011). In some embodiments, the tumor immunotherapeutic agent is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

In some embodiments, the tumor immunotherapy agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).

In some embodiments, the tumor immunotherapy agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, the tumor immunotherapy agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12/32433).

In some embodiments, the tumor immunotherapy agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, the tumor immunotherapy agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from the group consisting of epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmatinib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, the tumor immunotherapy agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, the tumor immunotherapy agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, the tumor immunotherapy agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the tumor immunotherapy agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, the tumor immunotherapy agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

In some embodiments, the tumor immunotherapy agent is MGA271 (B7H3) (WO11/109400).

In some embodiments, the tumor immunotherapy agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, in Pilimuamab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, the tumor immunotherapy agent is an immunostimulant. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis have been shown in clinical trials to be able to release activated tumor-reactive T cells and induce durable anti-tumor responses in an increasing number of tumor histologies, including some tumor types not traditionally considered susceptible to immunotherapy. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (also known as Opdivo®, Bristol-Myers Squibb, ONO-4538, MDX1106, and BMS-936558) has shown potential to improve overall survival in patients with RCC who have experienced disease progression during or after prior antiangiogenic therapy.

In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); and ingenol mebutate (Picato®, LEO Pharma).

In some embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex/Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions of melanoma. In some embodiments, the tumor immunotherapy agent is an oncolytic virotherapy such as PexaVec/JX-594 (SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Biotech) (mutants of respiratory enterovirus that do not replicate in cells that are not activated by RAS in multiple cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322) and non-small cell lung cancer (NSCLC) (NCT00861627)); metastatic or advanced epithelial cancers, such as ovarian cancer (NCT02028117), colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036) Enadenotusileb (NG-348, PsiOxus, formerly known as ColoAd1) in tumors (an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein); ONCOS-102 (Targovax/formerly Oncos) in melanoma (NCT03003676), and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831) (an adenovirus engineered to express GM-CSF); GL-ONC1 (GLV-1h68/GLV-1h153, Genelux) in tumors (NCT03003676), and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831). GmbH) (vaccinia viruses engineered to express beta-galactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter (hNIS) were investigated in peritoneal carcinomatosis (NCT01443260); fallopian tube and ovarian cancers (NCT02759588), respectively); or CG0070 (Cold Genesys) (adenovirus engineered to express GM-CSF) in bladder cancer (NCT02365818).

In some embodiments, the immuno-oncology agents include JX-929 (SillaJen/formerly Jennerex Biotherapeutics) (TK and vaccinia growth factor deficient vaccinia virus engineered to express cytosine deaminase capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil); TG01 and TG02 (Targovax/formerly Oncos) (peptide-based immunotherapeutics targeting refractory RAS mutations); and TILT-123 (TILT and VSV-GP (ViraTherapeutics) (a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) and which may be further engineered to express antigens designed to enhance antigen-specific CD8 ⁺ T cell responses).

In some embodiments, the tumor immunotherapy agent is a T cell that has been engineered to express a chimeric antigen receptor, or CAR. Such T cells that have been engineered to express a chimeric antigen receptor are referred to as CAR-T cells.

CARs are constructed that consist of a binding domain, which can be derived from a single chain variable fragment (scFv) that is a natural ligand derived from a monoclonal antibody specific for a cell surface antigen, fused to a functional end endodomain of the T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, capable of generating an activation signal in T lymphocytes. Upon binding to an antigen, such a CAR links to an endogenous signaling pathway in the effector cell, generating an activation signal similar to that initiated by the TCR complex.

For example, in some embodiments, the CAR-T cell is one of those described in U.S. Pat. No. 8,906,682 (June et al.; incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds CD19) fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently underway using CAR-T in a wide range of indications [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, the immune stimulant is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that has a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of innate immune cell subsets that express IL-17, such as NK cells. In some embodiments, the activator is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, the immune stimulant is a toll-like receptor (TLR) agonist or activator. Suitable activators of TLR include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immune stimulatory CpG currently under investigation for follicular B cell and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), currently under investigation for squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

Other tumor immunotherapy agents that may be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; Pharma, AstraZeneca) anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), anti-MMP9 antibody; MK-4166 (Merck & Co.), anti-GITR monoclonal antibody.

In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, a toll-like receptor agonist or activator, and an activator of RORγt.

In some embodiments, the immune stimulating therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 is being tested in the clinic as a therapeutic agent for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888), and leukemia (NCT02689453). In some embodiments, the immune stimulating therapeutic agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

In some embodiments, the tumor immunoagent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunoagent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the tumor immunoagent is a small molecule that targets a tumor immunological target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the tumor immunoagent is a small molecule that targets a tumor immunological target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the tumor immunoagent is a small molecule that targets a tumor immunological target selected from those listed in Table 2 of Jerry L. Adams et al. A small molecule drug selected from those listed in Table 2.

In some embodiments, the tumor immunotherapy agent is selected from the small molecule tumor immunotherapy agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapy agent is an agent that targets a pathway described in Peter L. Toogood.

In some embodiments, the tumor immunotherapy agent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing", PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapy agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates the T cell. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates the T cell, which releases cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates the T cell, which results in induction of bystander cell lysis. In some embodiments, the bystander cells are in a solid tumor. In some embodiments, the bystander cells that lyse are in the vicinity of the BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor associated antigen (TAA) negative cancer cells. In some embodiments, the bystander cells comprise EGFR negative cancer cells. In some embodiments, the tumor immunoagent is an antibody that blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, the tumor immunoagent is an ex vivo expanded tumor infiltrating T cell. In some embodiments, the tumor immunoagent is a bispecific antibody construct or a chimeric antibody receptor (CAR) that directly connects T cells to tumor associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors In some embodiments, the tumor immunotherapy agent is an immune checkpoint inhibitor as described herein.

The term "checkpoint inhibitors", as used herein, relates to agents useful for preventing cancer cells from evading the patient's immune system. One of the main mechanisms of antitumor immune destruction is known as "T cell exhaustion", which results from prolonged exposure to antigens that leads to the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent indiscriminate immune responses.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activation gene-3 (Lag-3; CD223) are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

In some embodiments, the immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) and blocks the receptor from binding to the inhibitory ligand PDL-1, thus abolishing the ability of the tumor to suppress the host's anti-tumor immune response.

In some embodiments, the checkpoint inhibitor is a biotherapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family of ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a ligand of the B-7 family, or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In additional aspects, the vaccine is a dendritic cell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors can include small molecule inhibitors, or can include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary immune checkpoint molecules that can be targeted for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (a member of the CD2 family of molecules expressed on all NK, gamma delta, and memory CD8 ⁺ (alpha beta) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various ligands of the B-7 family. Ligands of the B7 family include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Exemplary immune checkpoint inhibitors include, but are not limited to, tremelimumab (CTLA-4 blocking antibody) (anti-OX40), PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), or tremelimumab.

In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron) (an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech) (an antibody that binds to PD-1, also known as CT-011), in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck), in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer). KGaA) (also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody); or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced, metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been investigated in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody currently being investigated in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody currently under investigation in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody currently under investigation in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody currently under investigation in advanced malignancies (NCT02608268).

In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is currently being investigated in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), also an anti-LAG-3 antibody, is currently being investigated in malignancies (NCT03005782). IMP321 (Immutep S.A.) is a LAG-3-Ig fusion protein that has been investigated in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists currently under investigation in clinical trials include PF-04518600/PF-8600 (Pfizer) (agonistic anti-OX40 antibodies) in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck) (agonistic anti-OX40 antibody) in Phase 1 clinical trials for cancer (NCT02528357); MOX40 in advanced solid tumors (NCT02318394 and NCT02705482); These include EDI0562 (Medimmune/AstraZeneca) (agonistic anti-OX40 antibody); MEDI6469 (agonistic anti-OX40 antibody) (Medimmune/AstraZeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) (agonistic anti-OX40 antibody) in advanced cancers (NCT02737475).

Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists currently being investigated in clinical trials include utomirumab (PF-05082566, Pfizer) (agonistic anti-CD137 antibody) in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb) (agonistic anti-CD137 antibody) in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass) in metastatic or locally advanced malignancies (NCT03881488). Therapeutics (agonistic anti-CD137 antibody).

Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists currently under investigation in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics), an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists currently under investigation in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); These include GWN323 (Novartis) (agonistic anti-GITR antibody) in advanced cancers (NCT02740270); INCAGN01876 (Incyte/Agenus) (agonistic anti-GITR antibody) in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck) (agonistic anti-GITR antibody) in solid tumors (NCT02132754), and MEDI1873 (Medimmune/AstraZeneca) (agonistic hexameric GITR ligand molecule with human IgG1 Fc domain) in advanced solid tumors (NCT02583165).

Other checkpoint inhibitors that can be used in the present invention include inducible T cell costimulatory agent (ICOS, also known as CD278) agonists. ICOS agonists currently being investigated in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphoma (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in a Phase 1 trial (NCT02723955); and JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in a Phase 1 trial (NCT02904226).

Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors currently being investigated in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb) (anti-KIR antibody) in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263) and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma) in lymphoma (NCT02593045). Pharma) (anti-KIR antibody that binds to the three domains of the long cytoplasmic tail (KIR3DL2)).

Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors currently being investigated in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and blocks CD47/SIRPa-mediated signaling, in a Phase 1 trial (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein generated by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which binds to human CD47 and blocks human CD47 from its "don't eat me" message, in Phase 1 clinical trials (NCT02890368 and NCT02663518). These include CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors currently being investigated in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING currently being investigated in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 trials (NCT02675439 and NCT03172936).

Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors currently under investigation in clinical trials include pexidartinib (PLX3397, Plexxikon) (a CSF1R small molecule inhibitor) in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumors (GIST) and ovarian cancer (NCT02452424); and pexidartinib (PLX3397, Plexxikon) (a CSF1R small molecule inhibitor) in pancreatic cancer (NCT03153410), melanoma (NCT031012 54) and solid tumors (NCT02718911); IMC-CS4 (LY3022855, Lilly) (anti-CSF-1R antibody); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis) (an orally available inhibitor of CSF1R) in advanced solid tumors (NCT02829723).

Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors currently being investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

Example Abbreviations Ac: Acetyl AcOH: Acetic acid ACN: Acetonitrile Ad: Adamantyl AIBN: 2,2'-Azobisisobutyronitrile Anhyd: Anhydrous Aq: Aqueous B ₂ Pin ₂ : Bis(pinacolato)diboron-4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BH ₃ : Borane Bn: Benzyl Boc: tert-butoxycarbonyl Boc ₂ O: di-tert-butyl dicarbonate BPO: benzoyl peroxide
ⁿ BuOH: n-butanol CDI: Carbonyldiimidazole COD: Cyclooctadiene d: day DABCO: 1,4-diazabicyclo[2.2.2]octane DAST: Dimethylaminosulfur trifluoride dba: Dibenzylideneacetone DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DCM: Dichloromethane DEA: Diethylamine DHP: Dihydropyran DIBAL-H: Diisobutylammonium hydride DIPA: Diisopropylamine DIPEA or DIEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMSO-dimethylsulfoxide DPPA: Diphenylphosphoryl azide dppf: 1,1'-bis(diphenylphosphino)ferrocene EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ee: Enantiomeric excess ESI: Electrospray ionization EA: Ethyl acetate EtOAc: Ethyl acetate EtOH: Ethanol FA: Formic acid h or hrs: Hours HATU: N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HCl: Hydrochloric acid HPLC: High performance liquid chromatography HOAc: Acetic acid IBX: 2-iodoxybenzoic acid IPA: Isopropyl alcohol KHMDS: Potassium hexamethyldisilazide K ₂ CO ₃ : Potassium carbonate LAH: Lithium aluminum hydride LDA: Lithium diisopropylamide m-CPBA: Meta-chloroperbenzoic acid M: Molar concentration MeCN: Acetonitrile MeOH: Methanol Me ₂ S: Dimethylsulfide MeONa: Sodium methylate MeI: Iodomethane min: Minutes mL: Milliliters mM: Millimole concentration mmol: Millimole MPa: Megapascals MOMCl: Methyl chloromethyl ether MsCl: Methanesulfonyl chloride MTBE: Methyl tert-butyl ether nBuLi: n-Butyl lithium NaNO ₂ : Sodium nitrite NaOH: Sodium hydroxide Na ₂ SO ₄ : Sodium sulfate NBS: N-Bromosuccinimide NCS: N-chlorosuccinimide NFSI: N-fluorobenzenesulfonimide NMO: N-methylmorpholine N-oxide NMP: N-methylpyrrolidine NMR: Nuclear Magnetic Resonance °C: Degrees Celsius Pd/C: Palladium on carbon Pd(OAc) ₂ : Palladium acetate PBS: Phosphate buffered saline PE: Petroleum ether POCl ₃ : Phosphorus oxychloride PPh ₃ : Triphenylphosphine PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate Rel: Relative R.T. or rt: room temperature sat: saturated SEMCl: chloromethyl-2-trimethylsilyl ethyl ether SFC: supercritical fluid chromatography SOCl ₂ : sulfur dichloride tBuOK: potassium tert-butoxide TBAB: tetrabutylammonium bromide TBAI: tetrabutylammonium iodide TEA: triethylamine Tf: trifluoromethanesulfonate TfAA, TFMSA or Tf ₂ O: trifluoromethanesulfonic anhydride TFA: trifluoroacetic acid TIPS: triisopropylsilyl THF: tetrahydrofuran THP: tetrahydropyran TLC: thin layer chromatography TMEDA: tetramethylethylenediamine pTSA: para-toluenesulfonic acid wt: weight Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods The following examples are intended to be illustrative of the invention and should not be construed as limiting thereto. Temperatures are given in degrees Celsius. Unless otherwise noted, all solvent evaporations are carried out under reduced pressure, preferably between about 15 mmHg and 100 mmHg (=20-133 mbar). The structure of final products, intermediates and starting materials may be confirmed by standard analytical methods, e.g. microanalysis and spectroscopic characterization, e.g. MS, IR, NMR, such as those exemplified below. Abbreviations used are conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwise noted.

Proton NMR ( ¹ H NMR) was performed in deuterated solvents. In certain compounds disclosed herein, one or more ¹ H shifts overlap with residual proteo solvent signals. These signals are not reported in the experiments provided herein below.

For acidic LCMS data: LCMS were recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS2020 equipped with electrospray ionization and quadruple MS detector [ES+ve to obtain MH ⁺ ] and equipped with a Chromolith Flash RP-18e 25x2.0mm, eluting with 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). Other LCMS were recorded on an Agilent 1290 Infinity RRLC equipped with an Agilent 6120 Mass detector. The column can be a BEH C18 50x2.1mm, 1.7 micron. The column flow rate was 0.55 ml/min and the mobile phase used (A) may include 2 mM ammonium acetate in 0.1% formic acid in water, and (B) 0.1% formic acid in acetonitrile.

For basic LCMS data: LCMS were recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS 2020 equipped with electrospray ionization and quadruple MS detector [MH ⁺ given as ES+ve] and equipped with an Xbridge C18, 2.1×50 mm column packed with 5 mm of C18-coated silica, or a Kinetex EVO C18 2.1×30 mm column packed with 5 mm of C18-coated silica, eluting with 0.05 vol % NH ₃ ·H ₂ O in water (solvent A) and acetonitrile (solvent B).

HPLC Analysis Method: HPLC was performed on an X Bridge C18 150 x 4.6 mm, 5 micron. The column flow may be 1.0 ml/min and the mobile phase (A) may contain 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile.

Prep HPLC analytical methods: In some examples, compounds were purified on a Shimadzu LC-20AP and UV detector. The column used may include an X-BRIDGE C18 (250x19) mm, 5μ. The column flow may be 16.0 ml/min, and the mobile phase (A) may include 0.1% formic acid in water and (B) acetonitrile. The basic method used (A) 5 mM ammonium bicarbonate and 0.1% NH3 in water and (B) acetonitrile, or (A) 0.1% ammonium hydroxide in water and (B) acetonitrile. UV spectra were recorded at 202 nm and 254 nm.

NMR Methods: 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400 MHz/5 mm Probe (BBFO) or equivalent. Chemical shifts are reported in parts per million.

As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. Although the general methods illustrate the synthesis of certain compounds of the invention, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds as described herein.

Intermediates:
15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6,9,12-tetraoxapentadecanoic acid (Intermediate A1)

This intermediate was synthesized as previously described in WO 2020/113233 and US 2019/192668.

12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecanoic acid (Intermediate A2)

Step 1 - Dodec-11-ynoic acid. To a solution of dodec-11-yn-1-ol (700 mg, 3.84 mmol, CAS#18202-10-3) in acetone (10 mL) at 0 °C was added Jones reagent (3.7 mL, 9.6 mmol). The mixture was then stirred at 0 °C for 2 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with _brine , dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (500 mg, 66%) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.0 (br s, 1H), 2.72 (t, J = 2.6 Hz, 1H), 2.22 - 2.10 (m, 4H), 1.52 - 1.38 (m, 4H), 1.35 - 1.33 (m, 2H), 1.28 - 1.21 (m, 8H).

Step 2 - Benzyl dodec-11-ynoic acid. To a solution of dodec-11-ynoic acid (500 mg, 2.55 mmol) in DMF (10 mL) at 0° C. was added K ₂ CO ₃ (529 mg, 33.8 mmol) and BnBr (523 mg, 3.06 mmol). The mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1, v/v) to give the title compound (600 mg, 82%) as a colorless oil. ¹ H NMR: (400 MHz, DMSO- _d6 ) δ 7.44 - 7.25 (m, 5H), 5.08 (s, 2H), 2.72 (t, J = 2.6 Hz, 1H), 2.34 (t, J = 7.4 Hz, 2H), 2.13 (td, J = 6.8, 2.8 Hz, 2H), 1.57 - 1.49 (m, 2H), 1.48 - 1.38 (m, 2H), 1.37 - 1.29 (m, 2H), 1.25 - 1.20 (m, 8H).

Step 3 - benzyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-ynoate. A mixture of benzyl dodeca-11-ynoate (170 mg, 0.6 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (101 mg, 0.3 mmol, intermediate H), Pd(PPh ₃ ) ₂ Cl ₂ (42 mg, 0.06 mmol), CuI (12 mg, 0.06 mmol), Cs ₂ CO ₃ (488 mg, 1.5 mmol) and 4 Å molecular sieves (150 mg) in dry DMF (5 mL) was heated at 85 °C under microwave irradiation for 40 min. Upon completion, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/2, v/v) to give the title compound (80 mg, 44%) as a yellow solid. LCMS m/z = 544.4 [M+H] ⁺ ; ^1H NMR: (400 MHz, DMSO-d ₆ ) δ 11.1 (s, 1H), 7.43 - 7.28 (m, 5H), 7.10 (dd, J = 7.7, 1.3 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H). 5.38 (dd, J = 12.8, 5.4 Hz, 1H), 5.07 (s, 2H), 3.63 (s, 3H), 2.95 - 2.81 (m, 1H), 2.77 - 2.58 (m, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.60 - 1.48 (m, 4H), 1.45 - 1.35 (m, 2H), 1.33 - 1.21 (m, 8H).

Step 4 - 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecanoic acid. To a solution of benzyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-ynoate (80 mg, 0.15 mmol) in THF (5 mL) was added 10% Pd(OH) ₂ /C (16 mg) and 10% Pd/C (16 mg). The mixture was stirred under H ₂ (1 atm) at 35°C overnight. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (60 mg, 90%) as a white solid. LCMS m/z = 458.4 [M+H] ⁺ . ^1H NMR: (400 MHz, DMSO- _d6 ) δ 11.1 (s, 1H), 7.01 - 6.82 (m, 3H), 5.35 (dd, J = 12.6, 5.4 Hz, 1H), 3.54 (s, 3H), 2.95 - 2.82 (m, 3H), 2.76 - 2.58 (m, 2H), 2.18 (t, J = 7.3 Hz, 2H), 2.05 - 1.94 (m, 1H), 1.64 - 1.53 (m, 2H), 1.53 - 1.42 (m, 2H), 1.42 - 1.70 (m, 14H).

9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)nonanoic acid (Intermediate A3)

This intermediate was synthesized as previously described in WO 2020/206424.

2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)acetic acid (Intermediate A4)

Step 1 - 2-(2-(prop-2-yn-1-yloxy)ethoxy)tert-butyl acetate. To a solution of 2-(prop-2-yn-1-yloxy)ethan-1-ol (500 mg, 4.99 mmol, CAS# 3973-18-0) in dry THF (8 mL) at 0 °C under _N2 , NaH (60% w/w dispersion in oil, 339.6 mg, 8.49 mmol) was added portionwise and the mixture was stirred at 0 °C for 1 h. Then 2-bromoacetate tert-butyl (974.1 mg, 4.99 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion, the reaction was quenched with sat. aq. _NH4Cl solution and the mixture was extracted with EtOAc (20 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1 to 20/1, v/v) to give the title compound (220 mg, 21%) as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.21 (d, J = 2.4 Hz, 2H), 4.02 (s, 2H), 3.74 (s, 4H), 2.42 (t, J = 2.4 Hz, 1H), 1.47 (s, 9H).

Step 2 - 2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)tert-butyl acetate. A mixture of 2-(2-(prop-2-yn-1-yloxy)ethoxy)tert-butyl acetate (126.4 mg, 0.59 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 0.30 mmol, intermediate H), Pd(PPh ₃ )Cl ₂ (41.4 mg, 0.059 mmol), CuI (11.2 mg, 0.059 mmol), Cs ₂ CO ₃ (479.4 mg, 1.48 g) and 4 Å molecular sieves (150 mg) in dry DMF (8 mL) was heated at 85° C. under microwave irradiation for 40 min. On completion, the mixture was poured into water and extracted with EtOAc (20 mL×4). The combined organic phase was washed with water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/2, v/v) to give the title compound (110 mg, 79%) as a yellow solid. LCMS m/z=470.1 [M−H] ⁻ .

Step 3 - 2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)tert-butyl acetate. To a solution of 2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)tert-butyl acetate (110 mg, 0.23 mmol) in THF (4 mL) was added 10% Pd/C (10 mg) and 10% Pd(OH) ₂ /C (10 mg). The mixture was stirred at 35° C. under H ₂ (1 atm) overnight. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (90 mg, 81%) as a yellow oil. LCMS m/z = 474.2 [M−H] ⁻ .

Step 4 - 2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)acetic acid. To a solution of tert-butyl 2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)acetate (90 mg) in DCM (3 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature under _N2 for 6 hours. Upon completion, the mixture was concentrated under reduced pressure and the residue was triturated with _Et2O to afford the title compound (80 mg, 100%) as a brown solid. LCMS m/z = 418.2 [M-H] ^- .

15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6,9,12-tetraoxapentadecanoic acid (Intermediate B1)

This intermediate was synthesized as previously described in WO 2020/206424, WO 2020/113233, and US 2019/0192668.

12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecanoic acid (Intermediate B2)

Step 1 - benzyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-ynoate. A mixture of benzyl dodeca-11-ynoate A2-2 (226 mg, 0.79 mmol, synthesized by steps 1-2 of intermediate A2), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (150 mg, 0.44 mmol, intermediate J), Pd(PPh ₃ ) ₂ Cl ₂ (63 mg, 0.09 mmol), CuI (17 mg, 0.09 mmol), Cs ₂ CO ₃ (716 mg, 2.2 mmol) and 4 Å molecular sieves (150 mg) in dry DMF (5 mL) was heated under microwave irradiation at 85° C. for 40 min. Upon completion, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/2, v/v) to give the title compound (130 mg, 54%) as a yellow solid. LCMS m/z = 566.4 [M+Na] ⁺ , ^1H NMR: (400 MHz, DMSO-d ₆ ) δ 11.1 (s, 1H), 7.38 - 7.28 (m, 5H), 7.21 (s, 1H), 7.08 - 7.06 (m, 2H), 5.35 (dd, J = 12.8, 5.4 Hz, 1H), 5.07 (s, 2H), 3.32 (s, 3H), 2.95 - 2.81 (m, 1H), 2.75 - 2.56 (m, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.03 - 1.96 (m, 1H), 1.58 - 1.47 (m, 4H), 1.43 - 1.34 (m, 2H), 1.32 - 1.18 (m, 8H).

Step 2 - 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecanoic acid. To a solution of benzyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-ynoate (130 mg, 0.24 mmol) in THF (5 mL) was added 10% Pd(OH) ₂ /C (26 mg) and 10% Pd/C (26 mg). The mixture was stirred under _H2 (1 atm) at 35°C overnight. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (100 mg, 92%) as a white solid. LCMS: m/z = 458.4 [M+H] ^<+> .

9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)nonanoic acid (Intermediate B3)

Step 1 - 3-[5-(9-hydroxynon-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione. To a solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (12 g, 36 mmol, Intermediate J) and non-8-yn-1-ol (14.93 g, 106.5 mmol, CAS# 10160-28-8) in TEA (30.00 mL, 215.8 mmol) and DMSO (60.00 mL, 844.7 mmol) was added CuI (675.83 mg, 3.549 mmol) and Pd( _PPh3 ) ₄ (4.10 g, 3.55 mmol). After stirring at 85° C. under nitrogen atmosphere for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (Column: Spherical C18, 20-40 um, 330 g; Mobile phase A: water (plus 10 mM FA); Mobile phase B: ACN; Flow rate: 80 mL/min; Gradient: 5% to 5% B for 10 min, 30% B to 45% B for 20 min; Detector: 254 nm; Fractions containing the desired product were collected at 36% B) and concentrated under reduced pressure to give the title compound (9 g, 64% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.11 (s, 1H), 7.23 (s, 1H), 7.11-7.07 (m, 2H), 5.38 (dd, J = 12.8, 5.3 Hz, 1H), 4.35-4.31 (m, 1H), 3.42-3.35 (m, 2H), 3.34 (s, 3H), 2.92-3.88 (m, 1H), 2.77-2.57 (m, 2H), 2.41 (t, J = 7.1 Hz, 2H), 2.09-1.98 (m, 1H), 1.57-1.53 (m, 2H), 1.48-1.23 (m, 8H). LC/MS(ESI, m/z): [(M - 1)] ^- = 396.2.

Step 2 - 3-[5-(9-hydroxynonyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione. To a stirred solution of 3-[5-(9-hydroxynon-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione (9.00 g, 22.6 mmol) in MeOH (1.00 L) was added Pd/C (2.00 g, 1.88 mmol, 10 wt%) at room temperature. The reaction mixture was purged with hydrogen three times and stirred at room temperature under hydrogen atmosphere for 3 hours. Upon completion, the reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound (9 g, 99% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.02-6.99 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.35-4.30 (m, 1H), 3.39-3.35 (m, 2H), 3.32 (s, 3H), 2.95-2.84 (m, 1H), 2.73-2.58 (m, 4H), 2.02-1.98 (m, 1H), 1.62-1.57 (m, 2H), 1.39-1.27 (m, 12H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 402.3.

Step 3 - 9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)nonanoic acid. To a solution of 3-(5-(9-hydroxynonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 249 μmol) in MeCN/H ₂ O (10/1, 5.0 mL) was added PIDA (401 mg, 1.25 mmol) and TEMPO (7.78 mg, 49.8 μmol) and the mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15/1, v/v) to give the title compound (92 mg, 89%) as a pink solid. LCMS: m/z = 416.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.0 (br s, 1H), 11.1 (s, 1H), 6.97 - 6.93 (m, 2H), 6.87 - 6.83 (m, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 3.54 (s, 3H), 2.92 - 2.83 (m, 3H), 2.75 - 2.57 (m, 2H), 2.18 (t, J = 7.4 Hz, 2H), 2.04 - 1.92 (m, 1H), 1.63 - 1.53 (m, 2H), 1.53 - 1.43 (m, 2H), 1.41 - 1.21 (m, 8H).

2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)acetic acid (Intermediate B4)

This intermediate was synthesized as previously described in WO 2020/206424 and US 2019/192668.

14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecanoic acid (Intermediate C1)

This intermediate was synthesized as previously described in WO 2020/113233 and US 2019/192668.

12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoic acid (Intermediate C2)

To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.87 g, 8.7 mmol, CAS#835616-60-9) in NMP (20 mL) was added 12-aminododecanoic acid (2.0 g, 7.2 mmol, CAS#693-57-2) and DIEA (1.87 g, 14.5 mmol). The mixture was heated at 90° C. overnight. Upon completion, the reaction mixture was allowed to cool to room temperature and purified directly by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 40/60, v/v, 0.1% HCOOH) to give the title compound (1.4 g, 41%) as a yellow solid. LCMS: m/z = 472.4 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 12.2 (br s, 1H), 11.1 (s, 1H), 7.57 (dd, J = 8.4, 7.2 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.51 (t, J = 5.8 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 3.31 - 3.23 (m, 3H), 2.95 - 2.82 (m, 1H), 2.63 - 2.53 (m, 1H), 2.17 (t, J = 7.4 Hz, 2H), 2.10 - 1.96 (m, 1H), 1.65 - 1.41 (m, 4H), 1.41 - 1.20 (m, 14H).

8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoic acid (Intermediate C3)

To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.00 g, 3.62 mmol, CAS#835616-60-9) in NMP (18 mL) was added 8-aminooctanoic acid (0.69 g, 4.34 mmol, CAS#1002-57-9) and DIEA (1.40 g, 10.9 mmol). The mixture was heated at 90 ° _C overnight. Upon completion, the reaction mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 40/60, v/v, 0.1% HCOOH) to give the title compound (0.8 g, 53%) as a light green solid. LCMS: m/z = 416.2 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.1 (s, 1H), 7.57 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.51 (t, J = 5.8 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 3.31 - 3.23 (m, 3H), 2.95 - 2.81 (m, 1H), 2.64 - 2.50 (m, 1H), 2.18 (t, J = 7.2 Hz, 2H), 2.08 - 1.95 (m, 1H), 1.62 - 1.40 (m, 4H), 1.37 - 1.08 (m, 6H).

2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetic acid (Intermediate C4)

This intermediate was synthesized as previously described in US 2019/0192668.

3-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate D1)

This intermediate was synthesized as previously described in US20190192668.

3-(4-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate D2)

Step 1 - Dodec-11-yn-1-yl 4-methylbenzenesulfonate. To a solution of dodec-11-yn-1-ol (200 mg, 517 μmol, CAS#18202-10-3) and TsCl (416 mg, 2.19 mmol) in DCM (5 mL) was added TEA (333 mg, 3.29 mmol) and DMAP (13.4 mg, 110 μmol). The mixture was stirred at room temperature under _N2 for 2 h. Upon completion, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1, v/v) to give the title compound (200 mg, 54%) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 4.01 (t, J = 6.5 Hz, 2H), 2.45 (s, 3H), 2.17 (td, J = 7.1, 2.6 Hz, 2H), 1.93 (t, J = 2.6 Hz, 1H), 1.68 - 1.57 (m, 2H), 1.55 - 1.46 (m, 2H), 1.42 - 1.32 (m, 2H), 1.31 - 1.18 (m, 10H).

Step 2 - 12-Azidododec-1-yne. To a solution of dodec-11-yn-1-yl 4-methylbenzenesulfonate (2.4 g, 7.1 mmol) in DMF (40 mL) was added _NaN3 (696 mg, _10.7 mmol) and the mixture was heated at 45 °C overnight. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (1.2 g, 81%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 3.25 (t, J = 7.0 Hz, 2H), 2.18 (td, J = 7.2, 2.6 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H), 1.65 - 1.47 (m, 6H), 1.44 - 1.23 (m, 10H).

Step 3 - Dodec-11-yn-1-amine. To a solution of 12-azidododec-1-yne (1.2 g, 5.79 mmol) in THF (30 mL) was added _PPh (1.82 g, 6.95 mmol) and H _O (104 mg, 5.79 mmol) and the mixture was stirred at room temperature overnight. Upon completion, the reaction was concentrated under reduced pressure and the residue was triturated with petroleum ether and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.0 g, 96%) as a colorless oil.

Step 4 - tert-Butyl dodec-11-yn-1-ylcarbamate. To a solution of dodec-11-yn-1-amine (1.0 g, 5.52 mmol) in DCM (30 mL) was added Boc ₂ O (1.44 g, 6.62 mmol) and TEA (1.11 g, 11.1 mmol) and the mixture was stirred at room temperature overnight. Upon completion, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 30/1, v/v) to give the title compound (1.2 g, 77%) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 6.74 (t, J = 5.2 Hz, 1H), 2.92 - 2.84 (m, 2H), 2.71 (t, J = 2.6 Hz, 1H), 2.13 (td, J = 6.8, 2.6 Hz, 2H), 1.45 - 1.29 (m, 16H), 1.23 (s, 9H).

Step 5 - tert-Butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)carbamate. A mixture of tert-butyl dodec-11-yn-1-ylcarbamate (249 mg, 887 μmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (150 mg, 443 μmol, intermediate H), Pd(PPh ₃ ) ₂ Cl ₂ (32.3 g, 88.7 μmol), CuI (16.8 mg, 88.7 μmol), Cs ₂ CO ₃ (719 mg, 2.21 mmol) and 4 Å molecular sieves (200 mg) in dry DMF (8.0 mL) was heated under microwave irradiation at 85° C. for 1 h. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15/1, v/v) to give the title compound (90 mg, 38%) as a colorless oil. LCMS m/z = 539.3 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.1 (s, 1H), 7.10 (dd, J = 7.7, 1.3 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.72 (t, J = 5.6 Hz, 1H), 5.37 (dd, J = 12.8, 5.2 Hz, 1H), 3.63 (s, 3H), 2.91 - 2.84 (m, 3H), 2.73 - 2.59 (m, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.61 - 1.53 (m, 2H), 1.46 - 1.39 (m, 2H), 1.36 - 1.26 (m, 12H), 1.24 (s, 9H).

Step 6 - tert-Butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecyl)carbamate. To a solution of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)carbamate (249 mg, 887 μmol) in THF (10.0 mL) was added 10% Pd/C (20 mg) and 10% Pd(OH) ₂ /C (20 mg). The mixture was stirred at 35° C. under H ₂ (1 atm) for 20 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (60 mg, 66%) as a white solid. LCMS m/z = 543.3 [M+H] ⁺ ; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.24 (br s, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 5.20 (dd, J = 12.3, 5.4 Hz, 1H), 3.66 (s, 3H), 3.16 - 3.04 (m, 2H), 2.93 - 2.83 (m, 3H), 2.32 - 2.16 (m, 2H), 2.08 - 1.82 (m, 3H), 1.66 - 1.59 (m, 4H), 1.51 - 1.24 (m, 23H).

Step 7 - 3-(4-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride. A mixture of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecyl)carbamate (60 mg, 110 umol) and a solution of 4M HCl in dioxane (10.0 mL) was stirred at room temperature for 3 hours. Upon completion, the mixture was concentrated under reduced pressure to give the title compound (50 mg, 96%) as a white solid. LCMS m/z = 443.2 [M+H] ⁺ .

3-(4-(9-aminononyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate D3)

Step 1 - tert-Butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]nona-8-yn-1-yl]carbamate. To a stirred mixture of 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate H) and tert-butyl N-(nona-8-yn-1-yl)carbamate (8.49 g, 35.5 mmol, intermediate O) in DMA (40.0 mL) and TEA (20.0 mL) was added Pd( _PPh3 ) ₄ (2.73 g, 2.37 mmol) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 3 hours. Upon completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse phase flash (Column: Spherical C18, 20-40 um, 330 g; Mobile phase A: Water (0.05% FA), Mobile phase B: ACN; Flow rate: 45 mL/min; Gradient (B%): 5%-5%, 8 min; 40%-60%, 30 min; 60%-95%; 0 min; 95%, 5 min; Detector: 254 nm; Rt: 23.4 min) to give the title compound (6.4 g, 55% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.11 (dd, J = 7.8, 1.3 Hz, 1H), 7.05 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 5.8 Hz, 1H), 5.39 (dd, J = 12.7, 5.4 Hz, 1H), 3.64 (s, 3H), 2.98-2.78 (m, 3H), 2.74-2.59 (m, 2H), 2.52-2.46 (m, 2H), 2.06-1.96 (m, 1H), 1.61-1.54 (m, 2H), 1.45-1.34 (m, 13H), 1.33-1.19 (m, 4H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 497.3.

Step 2 - tert-Butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]nonyl]carbamate. To a stirred mixture of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]non-8-yn-1-yl]carbamate (6.40 g, 12.9 mmol) in MeOH (500 mL) was added Pd/C (1371.48 mg, 12.887 mmol) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. Upon completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure to give the title compound (6.0 g) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.02-6.91 (m, 2H), 6.88-6.85 (m, 1H), 6.75 (t, J = 5.7 Hz, 1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 3.55 (s, 3H), 2.90-2.87 (m, 3H), 2.78-2.56 (m, 2H), 2.04-1.94 (m, 1H), 1.61-1.56 (m, 2H), 1.38-1.32 (m, 15H), 1.29-1.19 (m, 8H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 501.3.

Step 3 - 3-[4-(9-aminononyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]nonyl]carbamate (6.00 g, 12 mmol) in DCM (20.0 mL) was added HCl in 1,4-dioxane (4 M) (20.0 mL) at room temperature under nitrogen atmosphere and the solution was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to afford the title compound (3.9 g, 91% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.11 (s, 1H), 8.03 (broad, 3H), 7.03-6.91 (m, 2H), 6.89-6.86 (m, 1H), 5.40 (dd, J = 12.6, 5.4 Hz, 1H), 3.57 (s, 3H), 2.94-2.85 (m, 3H), 2.81-2.57 (m, 4H), 2.03-1.97 (m, 1H), 1.64-1.53 (m, 4H), 1.41-1.26 (m, 10H). LC/MS (ESI, m/z): [(M + 1)] ⁺ = 401.3.

3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate D4)

This intermediate was synthesized as previously described in WO 2020/113233 and US 2019/192668.

3-(4-(6-aminohexyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate D5)

Step 1 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hex-5-yn-1-yl]carbamate. To a stirred mixture of 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate H) and tert-butyl N-(hex-5-yn-1-yl)carbamate (7.00 g, 35.5 mmol) in DMA (40.00 mL) and TEA (20.00 mL) was added Pd( _PPh3 ) ₄ (2.73 g, 2.37 mmol) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 3 hours. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse phase flash using the following conditions (Column: Spherical C18, 20-40 um, 330 g; Mobile phase A: Water (0.05% FA), Mobile phase B: ACN; Flow rate: 45 mL/min; Gradient (B%): 5%-5%, 8 min; 40%-60%, 30 min; 60%-95%; 0 min; 95%, 5 min; Detector: 254 nm; Rt: 23.4 min) to give the title compound (4.5 g, 42% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.06 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.85 (t, J = 5.7 Hz, 1H), 5.39 (dd, J = 12.7, 5.3 Hz, 1H), 3.64 (s, 3H), 2.99-2.93 (m, 2H), 2.92-2.84 (m, 1H), 2.81-2.59 (m, 2H), 2.52-2.47 (m, 2H), 2.05-1.99 (m, 1H), 1.57-1.51 (m, 4H), 1.38 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 455.3.

Step 2 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hexyl]carbamate. To a stirred mixture of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hex-5-yn-1-yl]carbamate (5.50 g, 12.1 mmol) in MeOH (500.00 mL) was added Pd/C (1.29 g, 12.1 mmol) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. Upon completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure to give the title compound (5 g, 90% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 6.99-6.92 (m, 2H), 6.86 (dd, J = 5.5, 3.5 Hz, 1H), 6.77 (t, J = 5.6 Hz, 1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 3.55 (s, 3H), 2.92-2.85 (m, 5H), 2.79-2.56 (m, 2H), 2.03-1.99 (m, 1H), 1.61-1.56 (m, 2H), 1.37 (s, 13H), 1.34-1.29 (m, 2H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 459.3.

Step 3 - 3-[4-(6-aminohexyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hexyl]carbamate (5.00 g, 10.9 mmol) in DCM (20.0 mL) was added HCl in 1,4-dioxane (4 M) (20.0 mL) at room temperature under nitrogen atmosphere. The solution was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (3.9 g, 91% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.11 (s, 1H), 8.04 (broad, 3H), 7.08-6.91 (m, 2H), 6.90-6.86 (m, 1H), 5.40 (dd, J = 12.6, 5.4 Hz, 1H), 3.57 (s, 3H), 2.98-2.84 (m, 3H), 2.80-2.73 (m, 2H), 2.71-2.57 (m, 2H), 2.04-1.98 (m, 1H), 1.63-1.56 (m, 4H), 1.49-1.32 (m, 4H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 359.3.

3-(5-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate E1)

A mixture of tert-butyl (15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6,9,12-tetraoxapentadecyl)carbamate (50 mg, 84 μmol, synthesized as described in WO2019060693) and a solution of 4 M HCl in dioxane (10.0 mL) was stirred at room temperature for 3 hours. Upon completion, the mixture was concentrated under reduced pressure to provide the title compound (60 mg, >100%) as a yellow solid. LCMS m/z = 493.4 [M+H] ⁺ .

3-(5-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate E2)

Step 1 - tert-Butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-yn-1-yl)carbamate. A mixture of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 295 μmol, Intermediate J), tert-butyl dodec-11-yn-1-ylcarbamate (141 mg, 502 μmol, synthesized by steps 1-4 of Intermediate D2), Pd(PPh ₃ ) ₂ Cl ₂ (41.5 mg, 59 μmol), CuI (11.2 mg, 59 μmol), Cs ₂ CO ₃ (479 mg, 1.4 mmol) and 4 Å molecular sieves (200 mg) in dry DMF (8.0 mL) was heated at 85° C. under microwave irradiation for 1 h. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc ( ₁₀₀ mL x 2). The combined organic layers were washed with brine, dried over _Na2SO4 , and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 15/1, v/v) to give the title compound (65 mg, 41%) as a colorless oil. LCMS m/z = 539.3 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.1 (s, 1H), 7.22 (s, 1H), 7.10 - 7.05 (m, 2H), 6.73 (t, J = 5.2 Hz, 1H), 5.36 (dd, J = 12.8, 5.4 Hz, 1H), 3.34 (s, 3H), 2.92 - 2.84 (m, 3H), 2.74 - 2.59 (m, 2H), 2.40 (t, J = 7.0 Hz, 2H), 2.07 - 1.97 (m, 1H), 1.58 - 1.49 (m, 2H), 1.45 - 1.19 (m, 23H).

Step 2 - tert-Butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecyl)carbamate. To a solution of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-yn-1-yl)carbamate (100 mg, 185 μmol) in THF (10.0 mL) was added 10% Pd/C (20 mg) and 10% Pd(OH) ₂ /C (20 mg). The mixture was stirred at 35° C. under H ₂ (1 atm) for 20 h. Upon completion, the reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound (60 mg, 59%) as a white solid. LCMS m/z = 543.2 [M+H] ⁺ ; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (br s, 1H), 6.88 (dd, J = 8.1, 1.5 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.20 (dd, J = 12.5, 5.3 Hz, 1H), 3.42 (s, 3H), 3.15 - 3.01 (m, 2H), 2.99 - 2.68 (m, 3H), 2.67 - 2.60 (m, 2H), 2.29 - 2.18 (m, 1H), 1.64 - 1.59 (m, 2H), 1.44 (s, 12H), 1.36 - 1.23 (m, 15H).

Step 3 - 3-(5-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride. A mixture of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecyl)carbamate (60 mg, 110 μmol) and a solution of 4M HCl in dioxane (10.0 mL) was stirred at room temperature for 3 hours. Upon completion, the mixture was concentrated under reduced pressure to provide the title compound (60 mg, >100%) as a yellow solid. LCMS m/z = 443.3 [M+H] ⁺ .

3-(5-(9-aminononyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate E3)

Step 1 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-yn-1-yl]carbamate. To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate J) and tert-butyl nona-8-yn-1-ylcarbamate (9.33 g, 47.3 mmol, intermediate O) in DMSO (40.00 mL) and TEA (20.00 mL) was added Pd(PPh ₃ ) ₄ (2.73 g, 2.37 mmol) and CuI (450.55 mg, 2.366 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 hours. Upon completion, the reaction mixture was diluted with EtOAc (800 mL). The resulting mixture was washed with 4×400 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:2) to give the title compound (7.2 g, 67% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.23-7.21 (m, 1H), 7.10-7.06 (m, 2H), 6.75-6.72 (m, 1H), 5.36 (dd, J = 12.8, 5.3 Hz, 1H), 3.30 (s, 3H), 2.92-2.83 (m, 3H), 2.75-2.55 (m, 2H), 2.40 (t, J = 7.0 Hz, 2H), 2.06-1.98 (m, 1H), 1.57-1.50 (m, 2H), 1.43-1.34 (m, 13H), 1.31-1.23 (m, 4H). LC/MS(ESI, m/z): [(M+1-56)] ⁺ = 497.3.

Step 2 - tert-Butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]nonyl]carbamate. To a stirred solution of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]non-8-yn-1-yl]carbamate (7.00 g, 14.1 mmol) in MeOH (500.0 mL) was added Pd/C (2.00 g, 1.88 mmol, 10 wt%) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. Upon completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, ACN in water, 60% to 80% gradient over 25 min; detector, UV 254 nm) to give the title compound (7 g) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.07 (s, 1H), 7.05-6.96 (m, 2H), 6.87-6.84 (m, 1H), 6.78-6.69 (m, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.32 (s, 3H), 2.92-2.87 (m, 3H), 2.77-2.63 (m, 2H), 2.62-2.58 (m, 2H), 2.05-1.95 (m, 1H), 1.61-1.55 (m, 2H), 1.39-1.34 (s, 11H), 1.31-1.20 (m, 10H). LC/MS(ESI, m/z): [(M+1-56)] ⁺ = 501.3.

Step 3 - 3-[5-(9-aminononyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]nonyl]carbamate (6.00 g, 12.0 mmol) in DCM (15.00 mL) was added dropwise 4M HCl (gas) in 1,4-dioxane (15.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with Et ₂ O to afford the title compound (5 g, 96% yield) as an off-white solid. ^1H NMR (400 MHz, methanol- _d4 ) δ 7.06-7.00 (m, 2H), 6.97-6.94 (m, 1H), 5.33 (dd, J = 12.3, 5.4 Hz, 1H), 3.43 (s, 3H), 2.98-2.87 (m, 3H), 2.86-2.75 (m, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.21-2.15 (m, 1H), 1.75-1.59 (m, 4H), 1.45-1.30 (m, 10H). LC/MS (ESI, m/z): [(M + 1 - 56)] ⁺ = 401.3.

3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate E4)

This intermediate was synthesized as previously described in US 2019/192668 and WO 2020/010210.

3-(5-(6-aminohexyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate E5)

Step 1 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-yn-1-yl]carbamate. To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate J) and tert-butyl N-(hex-5-yn-1-yl)carbamate (9.33 g, 47.3 mmol, CAS#151978-58-4) in DMSO (40.0 mL) and TEA (20.0 mL) was added Pd(PPh ₃ ) ₄ (2.73 g, 2.37 mmol) and CuI (450.55 mg, 2.366 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 hours. Upon completion, the reaction mixture was diluted with EtOAc (800 mL) and washed with 4×400 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:2) to give the title compound (7.2 g, 67% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.24 (d, J = 1.2 Hz, 1H), 7.09 (d, J = 1.2 Hz, 2H), 6.83 (t, J = 5.7 Hz, 1H), 5.38 (dd, J = 12.7, 5.4 Hz, 1H), 3.34 (s, 3H), 2.97 (d, J = 5.1 Hz, 2H), 2.91-2.83 (m, 1H), 2.77-2.57 (m, 2H), 2.44-2.37 (m, 2H), 2.06-2.00 (m, 1H), 1.56-1.50 (m, 4H), 1.38 (s, 9H); LC/MS(ESI, m/z): [(M+1)] ⁺ = 355.3.

Step 2 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hexyl]carbamate. To a stirred solution of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-yn-1-yl]carbamate (6.00 g, 13.2 mmol) in MeOH (500 mL) was added Pd/C (1.97 g, 1.85 mmol, 10 wt%) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 48 hours. Upon completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, ACN in water, 60% to 80% gradient over 25 min; detector, UV 254 nm) to give the title compound (5 g, 83%) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.05-6.96 (m, 2H), 6.86 (m, 1H), 6.76-6.73 (m, 1H), 5.36-5.31 (m, 1H), 3.18 (d, J = 5.2 Hz, 1H), 2.92-2.86 (m, 3H), 2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.62-2.57 (m, 2H), 2.03-1.98 (m, 1H), 1.57 (d, J = 7.5 Hz, 2H), 1.39-1.34 (m, 13H), 1.32-1.25 (m, 4H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 359.2.

Step 3 - 3-[5-(6-aminohexyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hexyl]carbamate (4.8 g) in DCM (20 mL) was added dropwise 4M HCl (gas) in 1,4-dioxane (20 mL) at room temperature under nitrogen atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with Et ₂ O to give the title compound (4 g, 97% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 8.01 (broad, 3H), 7.07-6.97 (m, 2H), 6.88-6.85 (m, 1H), 5.36 (dd, J = 12.7, 5.4 Hz, 1H), 3.50-3.36 (m, 2H), 3.32 (s, 3H), 3.00-2.82 (m, 1H), 2.77-2.71 (m, 2H), 2.66-2.60 (m 2H), 2.05-1.94 (m, 1H), 1.62-1.51 (m, 4H), 1.42-1.18 (m, 4H).

4-((12-aminododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate F2)

Step 1 – (tert-Butyl (12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)carbamate. To a solution of tert-butyl (12-aminododecyl)carbamate (900 mg, 333 μmol, CAS# 109792-60-1) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (993 mg, 399 μmol, CAS# 835616-60-9) in DMF (15.0 mL), DIPEA (774 mg, 666 μmol) was added and the mixture was heated at 90 °C under _N2 overnight. Upon completion, the mixture was poured into water and extracted with DCM (10 mL × 3). The combined organic phases were dried _{over Na2SO4} and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/ _H2O , 60/40, v/v, 0.1% HCOOH) to give the title compound (586 mg, 54%) as a yellow-green semi-solid. LCMS m/z = 557.3 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.20 (br s, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.22 (t, J = 5.6 Hz, 1H), 4.91 (dd, J = 12.1, 5.3 Hz, 1H), 4.51 (br s, 1H), 3.27 - 3.23 (m, 2H), 3.15 - 3.03 (m, 2H), 2.92 - 2.67 (m, 3H), 2.18 - 2.08 (m, 1H), 1.69 - 1.65 (m, 2H), 1.44 (s, 12H), 1.33 - 1.23 (m, 15H).

Step 2 - 4-((12-aminododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)carbamate (140 mg, 252 umol) and a solution of 4M HCl in dioxane (14.0 mL) was stirred at room temperature for 2 hours. Upon completion, the mixture was concentrated under reduced pressure to provide the title compound (118 mg, 96%) as a yellow oil. LCMS m/z = 457.3 [M+H] ⁺ .

4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate F3)

This intermediate was synthesized as previously described in US 2019/192668.

4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate F4)

Step 1 - (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate tert-Butyl (8-aminooctyl)carbamate (450 mg, 1.85 mmol, CAS# 88829-82-7) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (612 mg, 2.21 mmol, CAS# 835616-60-9) in DMF (8 mL) was added DIPEA (476.9 mg, 3.69 mmol) and the mixture was heated at 90 °C under _N2 overnight. Upon completion, the mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/ _H2O , 40/60, v/v, _0.1 % HCOOH) to give the title compound (350 mg, 38% yield) as a green semi-solid. LCMS: m/z = 501.25 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.1 (s, 1H), 7.60 - 7.55 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.74 (t, J = 5.2 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.30 - 3.26 (m, 2H), 2.97 - 2.79 (m, 4H), 2.63 - 2.52 (m, 2H), 1.41 - 1.27 (m, 21H).

Step 2 - 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate (350 mg, 0.70 mmol) and a solution of 4 M HCl in dioxane (8 mL) was stirred at room temperature for 1 hour. Upon completion, the mixture was concentrated under reduced pressure to afford the title compound (300 mg, 98% yield) as a green semi-solid. LCMS: m/z = 401.20 [M+H] ⁺ .

4-((9-aminononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate F5)

Step 1 - tert-Butyl N-(9-hydroxynonyl)carbamate. To a stirred solution of 9-aminononan-1-ol hydrochloride (42.00 g, 214.6 mmol) and TEA (59.5 mL, 429 mmol) in DCM (500.00 mL) was added Boc ₂ O (56.20 g, 257.5 mmol) portionwise at 0° C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Upon completion, the resulting mixture was diluted with water (300 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (300 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:1) to afford the title compound (53 g, 95% yield) as a colorless oil. ^1H NMR (400 MHz, chloroform-d) δ 4.58 (broad, 1H), 3.64-3.56 (m, 2H), 3.07 (t, J = 6.9 Hz, 2H), 1.54 (p, J = 7.6, 6.2 Hz, 2H), 1.46 (s, 9H), 1.34-1.24 (m, 12H); LC/MS(ESI, m/z): [(M - 1)] ⁺ = 258.3.

Step 2 - tert-Butyl N-[9-(methanesulfonyloxy)nonyl]carbamate. To a stirred solution of tert-butyl N-(9-hydroxynonyl)carbamate (50.00 g, 192.8 mmol) and TEA (54.54 mL, 385.5 mmol) in DCM (1.00 L) was added MsCl (33.12 g, 289.1 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting solution was stirred at room temperature under nitrogen atmosphere for 3 h. Upon completion, the resulting solution was diluted with water (500 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (200 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (66 g) as a yellow solid. ^1H NMR (400 MHz, chloroform-d) δ 4.52 (broad, 1H), 4.24 (t, J = 6.6 Hz, 2H), 3.17-3.05 (m, 2H), 3.02 (s, 3H), 1.82-1.69 (m, 2H), 1.53-1.39 (m, 14H), 1.33-1.24 (m, 8H); LC/MS(ESI, m/z): [(M - 1)] ⁺ = 336.1.

Step 3 - tert-Butyl N-(9-azidononyl)carbamate. A mixture of tert-butyl N-[9-(methanesulfonyloxy)nonyl]carbamate (66.00 g, 195.6 mmol) and NaN ₃ (22.88 g, 352.0 mmol) in DMF (400.0 mL) was stirred at 40° C. under nitrogen atmosphere for 4 h. Upon completion, the resulting mixture was allowed to cool to room temperature and diluted with water (800 mL). The resulting mixture was extracted with co-solvent (PE:EA=2:1) (2×1.5 L). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give the title compound (50.8 g, 91% yield) as a pale yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 6.71 (t, J = 5.6 Hz, 1H), 3.31 (t, J = 6.9 Hz, 2H), 2.90 (q, J = 6.6 Hz, 2H), 1.53 (p, J = 6.9 Hz, 2H), 1.40-1.36 (m, 11H), 1.29-1.24 (m, 10H).

Step 4 - tert-Butyl N-(9-aminononyl)carbamate. A solution of tert-butyl N-(9-azidononyl)carbamate (47.00 g, 165.3 mmol) and _PPh3 (47.68 g, 181.8 mmol) in THF (500.00 mL) and _H2O (50.00 mL) was stirred at 55°C under nitrogen atmosphere overnight. Upon completion, the solution was cooled to room temperature and concentrated under reduced pressure to give the title compound (100 g) as a white solid.

Step 5 - tert-Butyl N-(9-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]nonyl)carbamate. To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (481.03 mg, 1.741 mmol, CAS# 835616-60-9) and tert-butyl N-(9-aminononyl)carbamate (450.00 mg, 1.741 mmol) in DMA (8.00 mL) was added DIEA (450.14 mg, 3.483 mmol) dropwise. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 hours. Upon completion, the mixture was cooled to room temperature. The resulting mixture was diluted with water (800 mL) and extracted with EtOAc (2×1 L). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give the title compound (50 g, 18% yield) as a green semi-solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.55-7.52 (m, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.75 (t, J = 5.7 Hz, 1H), 6.52 (t, J = 5.9 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.29 (q, J = 6.7 Hz, 2H), 2.93-2.87 (m, 3H), 2.68-2.53 (m, 2H), 2.14-2.01 (m, 1H), 1.61-1.54 (m, 2H), 1.38-1.24 (m, 21H). LC/MS(ESI, m/z): [(M + 1)] ⁺ = 515.4.

Step 6 - 4-[(9-aminononyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride. To a stirred solution of tert-butyl N-(9-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]nonyl)carbamate (57.00 g, 111 mmol) in DCM (150 mL) was added dropwise 4M HCl (g) in 1,4-dioxane (150 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (400 mL) and stirred at room temperature under nitrogen atmosphere overnight. The precipitated solid was collected by filtration and dried under reduced pressure to provide the title compound (13 g, 26% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.94 (broad, 3H), 7.61-7.57 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.53 (t, J = 5.9 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 3.30 (q, J = 6.6 Hz, 2H), 2.92-2.88 (m, 1H), 2.75 (q, J = 7.3, 6.8 Hz, 2H), 2.62 (t, J = 3.6 Hz, 1H), 2.59-2.56 (m, 1H), 2.10-1.97 (m, 1H), 1.59-1.55 (m, 4H), 1.39-1.24 (m, 11H); LC/MS(ESI, m/z): [(M+1)] ⁺ = 415.2.

4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate F6)

This intermediate was synthesized as previously described in US 2019/192668.

4-((6-((4-aminopiperidin-1-yl)sulfonyl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate G1)

Step 1 - S-(6-(1,3-dioxoisoindolin-2-yl)hexyl ethanethioate. To a solution of 2-(6-bromohexyl)isoindoline-1,3-dione (3.0 g, 9.68 mmol, CAS# 24566-79-8) in DMF (90 mL) was added KSAc (3.31 g, 29.04 mmol) and the mixture was stirred at room temperature under _N2 for 2 h. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc ( ₅₀ mL x 3). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure to afford the title compound (2.3 g, 75% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.86 - 7.80 (m, 2H), 7.73 - 7.67 (m, 2H), 3.67 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.30 (s, 3H), 1.73 - 1.65 (m, 2H), 1.58 - 1.51 (m, 2H), 1.38 (m, 4H).

Step 2 - 6-(1,3-dioxoisoindolin-2-yl)hexane-1-sulfonyl chloride. To a solution of S-(6-(1,3-dioxoisoindolin-2-yl)hexyl)ethanethioate (1.0 g, 3.28 mmol) and 2 M aqueous HCl (2 mL) in MeCN (25.0 mL) at 0 °C, NCS (1.18 g, 8.81 mmol) was added portionwise and the mixture was allowed to warm to room temperature and stirred for 1 h. Upon completion, the mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (1.1 g, 80% yield) as an off-white solid. LCMS: m/z = 330.2 [M+H] ⁺ .

Step 3 - (1-((6-(1,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl. To a solution of 6-(1,3-dioxoisoindolin-2-yl)hexane-1-sulfonyl chloride (1.1 g, 3.34 mmol) and tert-butyl piperidin-4-ylcarbamate (668 mg, 3.34 mmol, CAS#73874-95-0) in DCM (20.0 mL) was added TEA (675 mg, 6.67 mmol) and the mixture was stirred at room temperature overnight. Upon completion, the solid was collected by filtration to afford the title compound (630 mg, 38 _% yield) as a white solid. The filtrate was diluted with water (30 mL), extracted with DCM (50 mL x 3) and the combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 65/35, v/v, 0.1% HCOOH) to give a further aliquot of the title compound (500 mg, 30% yield) as a white solid. LCMS: m/z = 494.2 [M+H] ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ 7.87 - 7.82 (m, 2H), 7.74 - 7.69 (m, 2H), 4.58 (br s, 1H), 3.77 - 3.63 (m, 4H), 3.58 (br s, 1H), 2.94 - 2.83 (m, 4H), 2.08 - 1.95 (m, 2H), 1.83 - 1.66 (m, 4H), 1.53 - 1.32 (m 15H).

Step 4 - tert-Butyl (1-((6-aminohexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((6-(1,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl)carbamate (900 mg, 1.82 mmol) in DCM/EtOH (2/1, 54.0 mL) was added N ₂ H ₄ ^.H ₂ O (98%, 365 mg, 7.29 mmol) and the mixture was heated at 50 °C overnight. Upon completion, the mixture was filtered and the filtrate was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was triturated with MeCN to afford the title compound (400 mg, 60%) as a white solid. LCMS: m/z = 364.2 [M+H] ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ 4.51 (br s, 1H), 3.74 (d, J = 12.4 Hz, 2H), 3.56 (br s, 1H), 2.92 - 2.84 (m, 4H), 2.69 (t, J = 6.8 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.83 - 1.76 (m, 2H), 1.52 - 1.33 (m, 17H).

Step 5 - tert-Butyl (1-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((6-aminohexyl)sulfonyl)piperidin-4-yl)carbamate (236 mg, 651.6 μmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (120 mg, 434.4 μmol, CAS# 835616-60-9) in NMP (5.0 mL) was added DIPEA (112.3 mg, 868.8 μmol) and the mixture was heated at 90° C. overnight. Upon completion, the mixture was directly purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 65/35, v/v, 0.1% HCOOH) to give the title compound (190 mg, 75%) as a yellow semi-solid. LCMS: m/z = 620.2 [M+H] ⁺ .

Step 6 - 4-((6-((4-aminopiperidin-1-yl)sulfonyl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (1-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 161.4 μmol) and a solution of 4M HCl in dioxane (6.0 mL) was stirred at room temperature for 5 hours. Upon completion, the mixture was concentrated under reduced pressure to provide the title compound (100 mg, >100%) as a yellow oil. LCMS: m/z = 520.2 [M+H] ⁺ .

4-((10-((4-aminopiperidin-1-yl)sulfonyl)decyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate G2)

Step 1 – S-(10-(1,3-dioxoisoindolin-2-yl)decyl ethanethioate. To a solution of 2-(10-bromodecyl)isoindoline-1,3-dione (2.0 g, 5.46 mmol, CAS# 24566-80-1) in DMF (20.0 mL) was added KSAc (686 mg, 6.01 mmol) and the mixture was stirred at room temperature under _N2 for 2 h. Upon completion, the mixture was poured into water and extracted with _EtOAc (30 mL x 3). The combined organic phase was dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (2.0 g, 100% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.84 (dd, J = 5.4, 3.2 Hz, 2H), 7.70 (dd, J = 5.6, 3.0 Hz, 2H), 3.67 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.70 - 1.60 (m, 2H), 1.59 - 1.50 (m, 2H), 1.35 - 1.25 (m, 12H).

Step 2 - 10-(1,3-dioxoisoindolin-2-yl)decane-1-sulfonyl chloride. To a solution of S-(10-(1,3-dioxoisoindolin-2-yl)hexyl)ethanethioate (200 mg, 0.55 mmol) and 2M aqueous HCl (0.15 mL) in MeCN (5.0 mL) at 0 °C, NCS (295.5 mg, 2.21 mmol) was added portionwise and the mixture was allowed to warm to room temperature and stirred for 1 h. Upon completion, the mixture was poured into ice-cold water and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (280 mg) as an off-white solid. LCMS: m/z = 386.1 [M+H] ⁺ .

Step 3 - tert-Butyl (1-((10-(1,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl piperidin-4-ylcarbamate (110.8 mg, 0.55 mmol, CAS# 73874-95-0) and Et ₃ N (675.0 mg, 6.67 mmol) in DCM (5.0 mL) at 0° C. was added a solution of 10-(1,3-dioxoisoindolin-2-yl)hexane-1-sulfonyl chloride (280 mg, estimated 0.55 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the mixture was concentrated under reduced pressure and the residue was triturated with MeOH. The solid was collected by filtration to give the title compound (40 mg, 13% for two steps) as a white solid. LCMS: m/z = 450.2 [M-Boc+H] ⁺ ; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.84 (dd, J = 5.4, 3.2 Hz, 2H), 7.70 (dd, J = 5.6, 3.2 Hz, 2H), 4.46 (br s, 1H), 3.79 - 3.71 (m, 2H), 3.67 (t, J = 7.2 Hz, 2H), 3.63 - 3.50 (m, 1H), 2.94 - 2.83 (m, 4H), 2.05 - 1.97 (m, 2H), 1.81 - 1.74 (m, 2H), 1.71 - 1.61 (m, 2H), 1.52 - 1.24 (m, 23H).

Step 4 - tert-Butyl (1-((10-aminohexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((10-(1,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl)carbamate (350 mg, 0.64 mmol) in DCM/EtOH (2/1, 15.0 mL) was added N ₂ H ₄ ^.H ₂ O (98%, 127.5 mg, 2.55 mmol) and the mixture was heated at 50 °C overnight. Upon completion, the mixture was filtered and the filtrate was poured into 1M aqueous NaOH and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was triturated with MeCN, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (160 mg, 60%) as a white solid. LCMS: m/z = 420.3 [M+H] ⁺ .

Step 5 - (1-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate. To a solution of (1-((10-aminohexyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (160 mg, 0.38 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (105.3 mg, 0.38 mmol, CAS# 835616-60-9) in NMP (3.0 mL) was added DIPEA (98.4 mg, 0.76 mmol) and the mixture was heated at 90° C. overnight. Upon completion, the mixture was allowed to cool to room temperature and purified directly by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 90/10, v/v, 0.1% HCOOH) to afford the title compound (40 mg, 16%) as a yellow solid. LCMS: m/z = 576.3 [M-Boc+H] ⁺ ; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (br s, 1H), 7.49 (dd, J = 8.4, 7.2 Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.22 (br s, 1H), 4.93 (d, J = 12.0, 5.3 Hz, 1H), 4.49 (br s, 1H), 3.81 - 3.68 (m, 2H), 3.63 - 3.50 (m, 1H), 3.26 (t, J = 7.0 Hz, 2H), 2.92 - 2.68 (m, 6H), 2.03 - 1.98 (m, 2H), 1.83 - 1.76 (m, 2H), 1.69 - 1.64 (m, 2H), 1.53 - 1.27 (m, 25H).

Step 6 - 4-((10-((4-aminopiperidin-1-yl)sulfonyl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (1-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate (36 mg, 0.053 mmol) and a solution of 4 M HCl in dioxane (6.0 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (30 mg, 94%) as a yellow oil. LCMS: m/z = 576.3 [M+H] ⁺ .

4-((14-((4-aminopiperidin-1-yl)sulfonyl)tetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Intermediate G3)

Step 1 - 2-(14-Bromotetradecyl)isoindoline-1,3-dione. To a solution of 1,14-dibromotetradecane (900 mg, 2.53 mmol, CAS# 37688-96-3) in DMF (20 mL) at room temperature, potassium phthalimide (471 mg, 2.53 mmol, CAS# 1074-82-4) was added and the mixture was stirred at 30 °C overnight. Upon completion, the mixture was poured into water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1, v/v) to give the title compound (600 mg, 56% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.92 - 7.77 (m, 4H), 3.59 - 3.47 (m, 6H), 1.85 - 1.70 (m, 4H), 1.62 - 1.53 (m, 2H), 1.40 - 1.31 (m, 4H), 1.28 - 1.24 (m, 12H).

Step 2 - S-(14-(1,3-dioxoisoindolin-2-yl)tetradecyl ethanethioate. To a solution of 2-(14-bromotetradecyl)isoindoline-1,3-dione (600 mg, 1.42 mmol) in DMF (20 mL) was added KSAc (485 mg, 4.26 mmol) and the mixture was stirred at room temperature for 2 h. Upon completion, the mixture was poured into water (100 mL) and extracted with EtOAc ( ₃₀ mL x 3). The combined organic phase was dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (550 mg, 93% yield) as a yellow solid. LCMS: m/z = 440.2 [M+Na] ⁺ .

Step 3 - 14-(1,3-dioxoisoindolin-2-yl)tetradecane-1-sulfonyl chloride. To a solution of S-(14-(1,3-dioxoisoindolin-2-yl)tetradecyl)ethanethioate (550 mg, 1.32 mmol) in MeCN (20 mL) at 0 °C was added 2 M aqueous HCl (2 mL) and NCS (705 mg, 5.28 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with saturated aqueous _NaHCO3 ( ₄₀ mL), dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (500 mg, 86% yield) as a yellow solid. LCMS: m/z = 442.2 [M+H] ⁺ .

Step 4 - tert-Butyl (1-((14-(1,3-dioxoisoindolin-2-yl)tetradecyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of 14-(1,3-dioxoisoindolin-2-yl)tetradecane-1-sulfonyl chloride (500 mg, 1.13 mmol) in DCM (10 mL) was added tert-butyl piperidin-4-ylcarbamate (272 mg, 1.36 mmol, CAS# 73874-95-0) and Et ₃ N (229 mg, 2.26 mmol) and the mixture was stirred at room temperature for 2 hours. Upon completion, the solvent was removed under reduced pressure and the residue was triturated with MeOH (20 mL), filtered and the filtrate was concentrated under reduced pressure to provide the title compound (300 mg, 44% yield) as a white solid. LCMS: m/z = 506.3 [M-Boc+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.89 - 7.80 (m, 4H), 6.88 (d, J = 8.0 Hz, 1H), 3.55 (t, J = 7.2 Hz, 2H), 3.52 - 3.45 (m, 3H), 3.00 - 2.93 (m, 2H), 2.89 - 2.80 (m, 2H), 1.82 - 1.71 (m, 2H), 1.69 - 1.51 (m, 4H), 1.46 - 1.18 (m, 31H).

Step 5 - tert-Butyl (1-((14-aminotetradecyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((14-(1,3-dioxoisoindolin-2-yl)tetradecyl)sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.50 mmol) in DCM/ethanol (5 mL/2.5 mL) was added N ₂ H ₄ ^.H ₂ O (98%, 250 mg, 5.0 mmol) and the mixture was heated at 50° C. for 2 days. Upon completion, the mixture was filtered and the filtrate was poured into water (50 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with saturated aqueous NaHCO ₃ (40 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (200 mg, 85% yield) as a white solid. LCMS: m/z = 476.4 [M+H] ⁺ .

Step 6 - tert-Butyl (1-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)tetradecyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((14-(1,3-dioxoisoindolin-2-yl)tetradecyl)sulfonyl)piperidin-4-yl)carbamate (200 mg, 0.42 mmol) in NMP (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (116 mg, 0.42 mmol, CAS# 835616-60-9) and DIPEA (108 mg, 0.84 mmol) and the mixture was heated at 90° C. overnight. Upon completion, the mixture was allowed to cool to room temperature and purified directly by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 92/8, v/v, 0.1% HCOOH) to give the title compound (140 mg, 46% yield) as a yellow solid. LCMS: m/z = 732.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.1 (s, 1H), 7.62 - 7.53 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.51 (t, J = 6.4 Hz, 1H), 5.04 (dd, J = 13.0, 5.2 Hz, 1H), 3.52 - 3.44 (m, 2H), 3.43 - 3.33 (m, 1H), 3.33 - 3.24 (m, 2H), 3.01 - 2.94 (m, 2H), 2.89 -2.80 (m, 3H), 2.62 - 2.51 (m, 1H), 2.17 (t, J = 8.2 Hz, 2H), 1.95 - 1.86 (m, 2H), 1.80 1.73 (m, 2H), 1.67 - 1.52 (m, 5H), 1.41 - 1.20 (m, 28H).

Step 7 - 4-((14-((4-aminopiperidin-1-yl)sulfonyl)tetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. To a solution of tert-butyl (1-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)tetradecyl)sulfonyl)piperidin-4-yl)carbamate (140 mg, 0.19 mmol) in dioxane (2 mL) was added a solution of 4 M HCl in dioxane (4 mL) and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was concentrated under reduced pressure to provide the title compound (110 mg, 88% yield) as a yellow solid. LCMS: m/z = 632.3 [M+H] ⁺ .

6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate L1)

Step 1 - tert-butyl 4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate. To a solution of 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (65 mg, 0.17 mmol, intermediate K) in 2-Me-THF (5 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (69.7 mg, 0.35 mmol, CAS# 87120-72-7) and the mixture was stirred at 30 °C overnight. Upon completion, the mixture was diluted with water and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/1, v/v) to give the title compound (40 mg, yield 47%) as a white solid. LCMS m/z = 492.2 [MH] ^- and 476.2 [ _MH2O +H] ⁺ ; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.72 (s, 1H), 8.05 (s, 2H), 6.85 (t, J = 55.4 Hz, 1H), 5.90 - 5.81 (m, 1H), 4.26 (br s, 1H), 4.08 - 3.87 (m, 2H), 3.23 - 3.17 (m, 1H), 2.94 - 2.81 (m, 2H), 2.26 - 2.14 (m, 1H), 2.07 - 1.79 (m, 6H), 1.76 - 1.63 (m, 1H), 1.54 - 1.38 (m, 11H), 1.00 (s, 3H).

Step 2 - 6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride. A mixture of tert-butyl 4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (160 mg, 0.32 mmol) and a solution of 4M HCl in dioxane (5 mL) was stirred at room temperature for 1 hour. Upon completion, the mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford the title compound (126 mg, 92%) as a yellow solid. LCMS m/z = 376.3 [M- _H2O +H] ⁺ .

4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride (Intermediate L2)

Step 1 - 2-((4-(benzylthio)-2-methylphenyl)amino)-6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one. A mixture of 4-(benzylthio)-2-methylaniline (590 mg, 2.6 mmol, Intermediate M), 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.3 mmol, Intermediate K) and TFA (1.48 g, 13 mmol) in isopropanol (20 mL) was heated to reflux for 6 hours. Upon completion, the mixture was allowed to cool to room temperature, poured _into water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc = 3/1, v/v) to give the title compound (200 mg, yield 29%) as a brown solid. LCMS m/z =523.3 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 7.40 - 7.15 (m, 8H), 6.89 (t, J = 55.2 Hz, 1H), 5.74 - 5.63 (m, 1H), 4.29 (s, 1H), 4.23 (s, 2H), 2.43 - 2.31 (m, 1H), 2.19 (s, 3H), 2.05 - 1.94 (m, 1H), 1.92 - 1.60 (m, 3H), 1.53 - 1.41 (m, 1H), 0.93 (s, 3H).

Step 2 - 4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride. To a solution of 2-((4-(benzylthio)-2-methylphenyl)amino)-6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.38 mmol) in MeCN (5 mL) at 0°C was added AcOH/water (0.4 mL/0.8 mL) and the mixture was stirred at 0°C for 5 minutes. Then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (150 mg, 0.76 mmol, CAS#118-52-5) was added and the mixture was stirred at 0° C. for an additional 30 min. Upon completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with saturated aqueous NaHCO ₃ (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (180 mg, 94% yield) as a brown solid. LCMS m/z = 499.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ) δ 9.50 (s, 1H), 8.84 (s, 1H), 8.14 (s, 1H), 7.49 - 7.41 (m, 2H), 7.26 - 7.21 (m, 1H), 6.89 (t, J = 55.2 Hz, 1H), 5.82 - 5.68 (m, 1H), 2.44 - 2.31 (m, 1H), 2.31 - 2.18 (m, 1H), 2.25 (s, 3H), 1.58 - 1.47 (m, 4H), 0.97 (s, 3H).

4-((5-bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride (Intermediate L3)

Step 1 - 2-((2-((4-(benzylthio)-2-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)-6-fluorobenzamide. A mixture of 4-(benzylthio)-2-methylaniline (2.0 g, 8.7 mmol, intermediate M), 2-((5-bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide (3.0 g, 8.7 mmol, intermediate N) and TFA (19.8 g, 87 mmol) in isopropanol (50 mL) was heated to reflux overnight. On completion, the mixture was allowed to cool to room temperature and poured into water (200 mL). The resulting precipitate was collected by filtration and washed with ether (20 mL x 3) to afford the title compound (1.8 g, 38% yield) as a white solid. LCMS m/z = 538.2, 540.2 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.2 (s, 1H), 8.78 (s, 1H), 8.20 (s, 1H), 8.16 - 8.04 (m, 3H), 7.42 - 7.28 (m, 5H), 7.28 - 7.20 (m, 2H), 7.16 (dd, J = 8.4, 2.4 Hz, 1H), 7.13 - 7.02 (m, 1H), 6.92 (t, J = 9.2 Hz, 1H), 4.23 (s, 2H), 2.14 (s, 3H).

Step 2 - 4-((5-Bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride. To a solution of 2-((2-((4-(benzylthio)-2-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)-6-fluorobenzamide (1.0 g, 1.86 mmol) in MeCN (20 mL) at 0° C. was added AcOH/H ₂ O (4 mL/8 mL) and the mixture was stirred at 0° C. for 5 minutes. Then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (733 mg, 3.72 mmol, CAS# 118-52-5) was added and the mixture was stirred at 0° C. for an additional 30 minutes. Upon completion, the mixture was diluted with EtOAc (200 mL), washed with _brine , dried over _Na2SO4 , and concentrated under reduced pressure. The residue was triturated with ether (10 mL x 3) to give the title compound (500 mg, 52% yield) as a white solid. LCMS m/z = 514.1, 516.1 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.9 (s, 1H), 9.86 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.1, 2.0 Hz, 1H), 7.38 - 7.27 (m, 3H), 7.07 (t, J = 9.2 Hz, 1H), 2.20 (s, 3H).

[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (Intermediate G)

Step 1 - 5-Oxotetrahydrofuran-2-carboxylic acid. To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS#617-65-2) in H ₂ O (800 mL) and HCl (12M, 210 mL) was added a solution of NaNO ₂ (147 g, 2.13 mol) in H ₂ O (400 mL) at -5 °C. The mixture was stirred at 15 °C for 12 h. Upon completion, the mixture was concentrated, then dissolved in EA (500 mL) and filtered and washed with EA (3 x 100 mL). The filtrate and washed solution were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (200 g, crude) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 6.43 (s, 1H), 5.02 - 4.95 (m, 1H), 2.67 - 2.38 (m, 4H).

Step 2 - N-[(4-Methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide. To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was added SOCl ₂ (246 g, 2.07 mol) slowly at 0 °C. The mixture was stirred at 85 °C for 3 h, then the mixture was stirred at 15 °C for 6 h. The mixture was concentrated in vacuum. The residue was dissolved in dry DCM (1 L) at 0 °C under N _2. Then, a solution of Et ₃ N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, then the mixture was stirred at 15 °C for 3 h. Upon completion, water (600 mL) was added and the mixture was extracted with DCM (3 x 300 mL). The combined organic phase was washed with 0.5 M HCl (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ 7.22 - 7.20 (d, J = 8.0, 1H), 6.89 - 6.87 (d, J = 8.0, 1H), 4.90 - 4.86 (m, 1H), 4.47 - 4.4.36 (m, 2H) 3.81 (s, 3H), 2.67 - 2.64 (m, 1H), 2.59 - 2.54 (m, 2H), 2.40 - 2.38 (m, 1H); LC-MS(ESI ⁺ ) m/z 272.0(M+Na) ⁺ .

Step 3 - 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. A solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to -78°C. Then, t-BuOK (62.7 g, 559 mmol) in a solution of anhydrous THF (1000 mL) was slowly added dropwise at -78°C under nitrogen atmosphere. The resulting reaction mixture was stirred at -40°C for 1 hour. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl solution (100 mL). The mixture was extracted with ethyl acetate (3 x 1500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (PE:EA=1:1) to give the title compound (128 g, 92% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.39 - 7.32 (m, 2H), 6.89 - 6.81 (m, 2H), 4.91 (s, 2H), 4.17 - 4.11 (m, 1H), 3.80 (s, 3H), 3.54 (s, 1H), 2.98 - 2.87 (m, 1H), 2.73 - 2.60 (m, 1H), 2.26 - 2.20 (m, 1H), 1.80 (dq, J = 4.8, 13.1 Hz, 1H).

Step 4 - [1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate. To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethanesulfonyl trifluoromethanesulfonate (73.0 g, 258 mmol) dropwise at 0° C. The mixture was stirred at -10° C. under N ₂ for 1.5 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA=20:1/8:1) to afford the title compound (45.0 g, 68% yield) as a pale yellow gum. ^1H NMR (400MHz, _CDCl3 ) δ 7.36 (d, J = 8.4 Hz, 2H), 6.85 - 6.82 (m, 2H), 5.32 - 5.28 (m, 1H), 4.91 (s, 2H), 3.79 (s, 3H), 3.02 - 2.97 (m, 1H), 2.79 - 2.74 (m, 1H), 2.41 - 2.35 (m, 2H).

3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate H)

Step 1 - 2-Bromo-N-methyl-6-nitro-aniline. To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS#58534-94-4) in THF (40 mL) was added MeNH ₂ (2M, 400 mL). The reaction mixture was stirred at 60°C for 12 h. Upon completion, the reaction mixture was poured into sat. NaHCO ₃ (30 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (40.0 g, 95% yield) as a red oil. LC-MS (ESI ⁺ ) m/z 230.9 (M+H) ⁺ .

Step 2 - 3-Bromo-N2-methyl-benzene-1,2-diamine. To a mixture of 2-bromo-N-methyl-6-nitro-aniline (23.0 g, 99.5 mmol) in EA (300 mL) and _H2O (10 mL) was added AcOH (100 mL). The mixture was warmed to 50 °C. Then Fe (22.2 g, 398 mmol) was added to the reaction mixture and the mixture was heated to 80 _° C for about 4 h. Upon completion, the reaction mixture was filtered and concentrated in vacuum. The residue was diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuum to give the title compound (20.0 g, 99% yield) as a red oil. ^1H NMR (400MHz, DMSO- _d6 ) δ 6.73 - 6.70 (m, 1H), 6.68 - 6.60 (m, 2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58 (s, 3H).

Step 3 - 4-Bromo-3-methyl-1H-benzimidazol-2-one. To a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4 mmol) in ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reaction mixture was stirred at 85 °C under _N2 atmosphere for 12 h. Upon completion, the reaction mixture was concentrated in vacuum. The reaction mixture was diluted with water (200 mL) and a solid precipitate was formed which was filtered off. The solid was washed with water (1 L) and dried in vacuum to give the title compound (20.0 g, 88% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.17 (s, 1H), 7.14 (dd, J = 1.2, 8.0 Hz, 1H), 7.00 - 6.95 (m, 1H), 6.93 - 6.87 (m, 1H), 3.55 (s, 3H).

Step 4 - 3-(4-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8 mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. Then, [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (20.1 g, 52.8 mmol, intermediate G) in a solution of THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at 20 °C under _N2 for 0.5 h. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (13.3 g, 55% yield) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ 7.38 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.80 (t, J = 8.0 Hz, 1H), 6.48 - 6.40 (d, J = 8.0 Hz, 1H), 5.22 (dd, J = 5.2, 12.8 Hz, 1H), 5.04 - 4.93 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.12 - 2.98 (m, 1H), 2.93 - 2.77 (m, 1H), 2.62 (dq, J = 4.4, 13.2 Hz, 1H), 2.20 - 2.17 (m, 1H).

Step 5 - 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. A mixture of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with _N2 three times, then the mixture was stirred at 120 °C under _N2 atmosphere for 2 hours. Upon completion, the reaction mixture was concentrated in vacuum to remove toluene. 200 mL of ice water was added to the residue, then a white precipitate formed. The mixture was filtered and the filter cake was collected and dried in vacuo to give the title compound (7.30 g, 74% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.05 - 6.93 (m, 1H), 5.41 (dd, J = 5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 2.96 - 2.83 (m, 1H), 2.78 - 2.59 (m, 2H), 2.08 - 2.00 (m, 1H).

5-Bromo-3-methyl-1H-benzimidazol-2-one (Intermediate I)

Step 1 - 5-Bromo-N-methyl-2-nitro-aniline. 4-Bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS# 321-23-3) was added to a solution of methylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 °C for 10 min. Upon completion, the mixture was diluted with H ₂ O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H).

Step 2 - 4-Bromo-N2-methyl-benzene-1,2-diamine. To a mixture of 5-bromo-N-methyl- ₂ -nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and H2O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50 °C and then Fe (174 g, 3.11 mol) was added to the reaction mixture. The reaction mixture was then stirred at 80 °C for 6 h. Upon completion, the mixture was filtered through Celite. The filtrate was concentrated in vacuum and the residue was diluted with _H2O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with aq. _NaHCO3 and brine (300 mL), dried over _{Na2SO4 ,} filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as a black oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.55 - 6.52 (m, 1H), 6.48 - 6.45 (m, 1H), 6.43 - 6.42 (m, 1H), 4.89 - 4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d, J = 4.0 Hz, 3H).

Step 3 - 5-Bromo-3-methyl-1H-benzimidazol-2-one. To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol) in CH ₃ CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture was stirred at 80 °C under N ₂ for 6 h. Upon completion, the mixture was concentrated in vacuum. The mixture was diluted with H ₂ O (1.0 L) and filtered. The filter cake was washed with water (3 x 200 mL) and dried in vacuum to give the title compound (106 g, 85% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.00 (s, 1H), 7.33 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H).

3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (Intermediate J)

Step 1 - 3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6 mmol, intermediate I) in THF (300 mL) was added t-BuOK (3.63 g, 32.3 mmol) at 0 °C. The mixture was stirred at 0-10 °C under _N2 for 1 h. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (9.87 g, 25.9 mmol, intermediate G) in THF (100 mL) was added to the reaction mixture at 0-10 °C over 30 min. The mixture was stirred at 0-10° C. under N ₂ for 30 min. An additional solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (2.47 g, 6.47 mmol) in THF (20 mL) was added dropwise to the reaction mixture at 0-10° C. The mixture was then stirred at 0-10° C. under N ₂ for another 30 min. Upon completion, the reaction was quenched with water (400 mL) and extracted with EA (3×200 mL). The combined organic layers were concentrated in vacuum. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuum to give the title compound (6.70 g, 67% yield) as a pale yellow solid. The filtrate was also concentrated in vacuum and the residue was purified by column chromatography to give another batch of the title compound (1.80 g, 18% yield) as a pale yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 7.47 (d, J = 1.6 Hz, 1H), 7.21 - 7.16 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 5.55 - 5.51 (m, 1H), 4.84 - 4.73 (m, 2H), 3.72 (s, 3H), 3.33 (s, 3H), 3.04 - 3.00 (m, 1H), 2.83 - 2.67 (m, 2H), 2.07 - 2.05 (m, 1H).

Step 2 - 3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione. To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was added methanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15 °C). The mixture was stirred at 120 °C for 2 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was poured into _ice /water (200 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuum. The residue was triturated with EA (80 mL) and filtered. The filtrate cake was collected and dried in vacuum to give the title compound (4.20 g, 67% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 5.40 - 5.35 (m, 1H), 2.34 (s, 3H), 2.92 - 2.88 (m, 1H), 2.71 - 2.60 (m, 2H), 2.03 - 1.99 (m, 1H).

6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate K)

Step 1 - (4-Chloro-2-(methylthio)pyrimidin-5-yl)methanol. To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (40.0 g, 172 mmol, CAS#5909-24-0) in THF (600 mL) at -78 °C under _N2 was added DIBAL-H (1 M in THF, 517 mL, 517 mmol) and the mixture was allowed to warm to room temperature and stirred for 0.5 h. Upon completion, the reaction was quenched with saturated aqueous _NH4Cl (1000 mL) and extracted with EtOAc ( ₁₀₀₀ mL x 2). The combined organic layers were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was triturated with petroleum ether to give the title compound (28.5 g, 87% yield) as a white solid. LCMS: m/z = 191.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 4.50 (s, 2H), 2.52 (s, 3H).

Step 2 - (1R,2R)-2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol. To a solution of (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (12.0 g, 63.0 mmol) in i-PrOH (200 mL) was added (1R,2R)-2-amino-1-methylcyclopentan-1-ol (7.96 g, 69.4 mmol, CAS# 1400689-45-3) and DIPEA (24.0 g, 189 mmol) and the mixture was heated at 90 °C under _N2 overnight. Upon completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1, v/v) to afford the title compound (11.0 g, 65% yield) as a white solid. LCMS: m/z = 270.2 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (s, 1H), 6.33 (d, J = 8.0 Hz, 1H), 5.29 (t, J = 5.3 Hz, 1H), 4.68 (s, 1H), 4.36 (d, J = 5.4 Hz, 2H), 4.33 - 4.23 (m, 1H), 2.42 (s, 3H), 2.19 - 2.10 (m, 1H), 1.72 - 1.55 (m, 4H), 1.52 - 1.41 (m, 1H), 1.09 (s, 3H).

Step 3 - 4-(((1R,2R)-2-Hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde. To a solution of (1R,2R)-2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (2.7 g, 10 mmol) in EtOAc (70 mL) was added _MnO2 (13.1 g, 150 mmol) and the mixture was heated at 50 °C under _N2 overnight. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (2.3 g, 86% yield) as a white solid. LCMS: m/z = 268.0 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.75 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.54 (s, 1H), 4.76 (s, 1H), 4.42 - 4.34 (m, 1H), 2.52 (s, 3H), 2.28 - 2.15 (m, 1H), 1.77 - 1.57 (m, 4H), 1.48 - 1.37 (m, 1H), 1.16 (s, 3H).

Step 4 - 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.3 g, 8.6 mmol) and EtOAc (2.27 g, 25.8 mmol) in dry THF (25 mL) was added LiHMDS (1 M in THF, 25.8 mL, 25.8 mmol) dropwise under _N2 at -10 °C. The mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction was quenched with saturated aqueous _NH4Cl and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with _brine , dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5/1, v/v) to give the title compound (2.1 g, yield 84%) as a yellow solid. LCMS: m/z = 291.9 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 7.89 (d, J = 9.4 Hz, 1H), 6.57 (d, J = 9.4 Hz, 1H), 5.93 - 5.84 (m, 1H), 4.53 (s, 1H), 2.60 (s, 3H), 2.45 - 2.34 (m, 1H), 2.26 - 2.15 (m, 1H), 2.04 - 1.94 (m, 1H), 1.91 - 1.82 (m, 2H), 1.71 - 1.64 (m, 1H), 0.95 (s, 3H).

Step 5 - 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)ethyl acetate. To a solution of 8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[ _{2,3-d]pyrimidin-7(8H)-one (100 mg, 0.34 mmol) in dry dioxane (5 mL) under N was added BrCF2COOEt (139.3 mg, 0.69 mmol, CAS#667-27-6), Pd(MeCN)2Cl2 ( 8.9 mg} , 0.034 _mmol ), Xantphos (39.7 mg, 0.069 mmol) and _K2CO3 (94.9 mg, 0.69 mmol) and the mixture was heated to reflux overnight. Upon completion, the mixture was allowed to cool to room temperature, poured into water and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=2/1, v/v) to give the title compound (70 mg, yield 49%) as a white solid. LCMS: m/z = 414.1 [M+H] ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ 8.73 (s, 1H), 8.03 (s, 1H), 5.91 - 5.85 (m, 1H), 4.41 - 4.31 (m, 2H), 2.79 - 2.68 (m, 1H), 2.65 (s, 3H), 2.29 - 2.19 (m, 1H), 2.11 - 1.88 (m, 3H), 1.85 - 1.78 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.12 (s, 3H).

Step 6 - 2,2-Difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetic acid. To a solution of 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)ethyl acetate (65 mg, 0.16 mmol) in MeOH/H ₂ O (4 mL/1 mL) was added K ₂ CO ₃ (43.5 mg, 0.31 mmol) and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was adjusted to pH 3 with 1M aqueous HCl and extracted with EtOAc (30 mL×4). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (50 mg, 82% yield) as a yellow solid. LCMS: m/z = 386.1 [M+H] ⁺ .

Step 7 - 6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetic acid (330 mg, 0.86 mmol) in NMP (10 mL) was added KF (248.5 mg, 4.28 mmol) and the mixture was heated at 150 °C for 2.5 h. Upon completion, the mixture was allowed to cool to room temperature, poured into water (50 mL) and extracted with EtOAc (50 mL x 4). The combined organic phase was washed with _brine , dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5/1, v/v) to give the title compound (110 mg, yield 38%) as a white solid. LCMS: m/z = 342.1 [M+H] ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ 8.71 (s, 1H), 7.94 (s, 1H), 6.80 (t, J = 54.8 Hz, 1H), 5.92 - 5.85 (m, 1H), 2.82 - 2.73 (m, 1H), 2.65 (s, 3H), 2.32 - 2.22 (m, 1H), 2.13 - 2.01 (m, 2H), 2.00 - 1.91 (m, 1H), 1.90 - 1.82 (m, 1H), 1.15 (s, 3H).

Step 8 - 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (110 mg, 0.32 mmol) in 2-Me-THF/H ₂ O (5 mL/1 mL) was added oxone (495.2 mg, 0.81 mmol) and the mixture was stirred at 30°C for 3 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/1, v/v) to give the title compound (60 mg, yield 50%) as a white solid. LCMS: m/z = 356.1 [ _MH2O +H] ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ 9.08 (s, 1H), 8.10 (s, 1H), 6.84 (t, J = 54.4 Hz, 1H), 5.85 - 5.76 (m, 1H), 3.41 (s, 3H), 2.82 - 2.72 (m, 1H), 2.35 - 2.24 (m, 1H), 2.18 - 2.07 (m, 2H), 2.02 - 1.88 (m, 2H), 1.13 (s, 3H).

4-(benzylthio)-2-methylaniline (intermediate M)

Step 1 - Benzyl(3-methyl-4-nitrophenyl)sulfane. To a solution of 4-chloro-2-methyl-1-nitrobenzene (10 g, 58 mmol, CAS#5367-28-2) in ethanol (200 mL) was added KOH (3.6 g, 64 mmol) and BnSH (7.9 g, 64 mmol, CAS#100-53-8) and the mixture was heated at 70° C. overnight. Upon completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1, v/v) to give the title compound (10 g, 67% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.93 (d, J = 8.6 Hz, 1H), 7.46 - 7.23 (m, 7H), 4.39 (s, 2H), 2.50 (s, 3H).

Step 2 - 4-(benzylthio)-2-methylaniline. To a solution of benzyl(3-methyl-4-nitrophenyl)sulfane (9.0 g, 34.7 mmol) in ethanol (100 mL) was added Fe (1.9 g, 347 mmol) and saturated aqueous NH ₄ Cl (50 mL) and the mixture was heated at 70° C. for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (7.0 g, 89% yield) as a brown solid. LCMS m/z = 230.2 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.30 - 7.16 (m, 5H), 6.95 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 8.2, 2.2 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 4.97 (s, 2H), 3.94 (s, 2H), 1.99 (s, 3H).

2-((5-Bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide (Intermediate N)

To a solution of 5-bromo-2,4-dichloropyrimidine (8.25 g, 36.2 mmol, CAS#36082-50-5) in isopropanol (50 mL) was added 2-amino-6-fluorobenzamide (5.02 g, 32.5 mmol, CAS#115643-59-9) and DIPEA (21.1 g, _162.9 mmol) and the mixture was heated to reflux under N for ₁₈ h. Upon completion, the mixture was allowed to cool to room temperature, dried over _Na2SO4 , and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1 to 3/1, v/v) to give the title compound (5.9 g, 48% yield) as a white solid. LCMS m/z = 345.0, 347.0 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.6 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.17 - 7.08 (m, 1H).

tert-Butyl nona-8-yn-1-ylcarbamate (Intermediate O)

Step 1 - Nona-8-yn-1-yl methanesulfonate. To a stirred solution of nona-8-yn-1-ol (20.00 g, 142.6 mmol) and TEA (39.54 mL, 285.3 mmol) in DCM (200.0 mL) was added MsCl (24.51 g, 213.9 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. Upon completion, the reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined organic layers were washed with NaCl aq (1 x 100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (30 g, 96% yield) as a pale yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 4.19 (t, J = 6.5 Hz, 2H), 3.16 (s, 3H), 2.73 (t, J = 2.7 Hz, 1H), 2.16 (td, J = 6.9, 2.7 Hz, 2H), 1.70-1.62 (m, 2H), 1.49-1.42 (m,2H), 1.40-1.26 (m, 6H).

Step 2 - 9-Azidonon-1-yne. To a stirred solution of non-8-yn-1-yl methanesulfonate (30.00 g, 137.4 mmol) in DMF (100.00 mL) was added NaN ₃ (17.87 g, 274.8 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 55°C for 16 h. Upon completion, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (30:1) to give 9-azidonon-1-yne (21 g, 92% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 3.37-3.27 (m, 2H), 2.73 (t, J = 2.8 Hz, 1H), 2.14 (td, J = 6.9, 2.6 Hz, 2H), 1.56-1.49 (m, 2H), 1.47-1.40 (m, 2H), 1.39-1.24 (m, 6H).

Step 3 - Nona-8-yn-1-amine hydrochloride. To a stirred solution of 9-azidonon-1-yne (32.00 g, 193.7 mmol) in THF (300.0 mL)/H ₂ O (30.00 mL) was added PPh ₃ (76.19 g, 290.5 mmol) portionwise at 0° C. under nitrogen atmosphere. The solution was stirred at 55° C. for 4 h. Upon completion, the solution was concentrated under reduced pressure and diluted with DCM (300 mL). The mixture was acidified to pH 1 with HCl (2 M aq.). The aqueous layer was extracted with DCM (3×100 mL). The aqueous layer was concentrated under reduced pressure to give the title compound (27 g, 79% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.04 (s, 3H), 2.81-2.68 (m, 3H), 2.15 (td, J = 6.9, 2.7 Hz, 2H), 1.59-1.51 (m, 2H), 1.50-1.39 (m, 2H), 1.39-1.23 (m, 6H). LC/MS (ESI, m/z): [(M + 1)] ⁺ = 140.2.

Step 4 - tert-Butyl N-(non-8-yn-1-yl)carbamate. To a stirred mixture of non-8-yn-1-amine hydrochloride (27.00 g, 153.7 mmol) in DCM (300.0 mL) was added TEA (106.5 mL, 768.4 mmol) dropwise at 0 °C under nitrogen atmosphere. Then Boc ₂ O (50.31 g, 230.5 mmol) was added dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. Upon completion, the reaction was quenched with water (200 mL) at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 100 mL) and the combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:1) to give the title compound (20 g, 54% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.76 (t, J = 5.7 Hz, 1H), 2.90 (q, J = 6.6 Hz, 2H), 2.73 (t, J = 2.6 Hz, 1H), 2.15 (td, J = 7.0, 2.7 Hz, 2H), 1.48-1.41 (m, 2H), 1.41-1.32 (m, 13H), 1.30-1.17 (m, 4H). LC/MS (ESI, m/z): [(M + 1 - 56)] ⁺ = 184.2.

(1R,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl phenyl carbonate (Intermediate P)

Step 1 - (1-(tert-butyl)-3-((1S,3R)-3-((phenoxycarbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of N-[2-tert-butyl-5-[(1S,3R)-3-hydroxycyclopentyl]pyrazol-3-yl]carbamate (1 g, 2.80 mmol, Intermediate AG) and phenyl carbonochloridate (394 mg, 2.52 mmol) in DCM (14 mL) was added DMAP (34.2 mg, 279 umol) and pyridine (663 mg, 8.39 mmol), then the mixture was stirred at 25°C for 12 hours. Upon completion, the mixture was washed with sat. The mixture was quenched with NH ₄ Cl (20 mL), diluted with DCM (20 mL), and then washed with water (20 mL×3) and brine (20 mL×3). The solution was then dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 0/1) to give the title compound (1.2 g, yield 85%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.48 - 7.29 (m, 7H), 7.27 - 7.15 (m, 3H), 6.13 (br s, 1H), 5.29 - 5.22 (m, 1H), 5.21 (s, 2H), 3.17 - 3.06 (m, 1H), 2.66 - 2.55 (m, 1H), 2.14 - 2.07 (m, 1H), 2.04 - 1.85 (m, 4H), 1.59 (s, 9H).

Step 2 - (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl phenyl carbonate. To a solution of (1-(tert-butyl)-3-((1S,3R)-3-((phenoxycarbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzylcarbamate (1 g, 2.09 mmol) in THF (25 mL) was added Pd/C (1.00 g, 943 umol, 10 wt%) and the reaction mixture was placed under an atmosphere _{of H2} . The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (0.7 g, 98% yield) as a colorless gum. LCMS: tR = 0.417 min, (ES ^<+> ) m/z (M+H) ^<+> = 344.2.

Step 3 - (1R,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl phenyl carbonate. A solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl phenyl carbonate (0.7 g, 2.04 mmol), 5-(methoxymethyl)-2-methyl-pyrazole-3-carboxylic acid (416 mg, 2.45 mmol, Intermediate AI), T ₃ P (3.89 g, 6.11 mmol, 50% solution in DMF) and DIEA (1.32 g, 10.2 mmol) in MeCN (8 mL) was stirred at 60°C for 12 hours. Upon completion, the mixture was washed with sat. It was quenched with NH ₄ Cl (10 mL) and extracted with EtOAc (15 mL×2). The organic layer was washed with brine (10 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (0.7 g, yield 62%) as a brown oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.44 (br s, 1H), 7.40 - 7.36 (m, 2H), 7.26 - 7.22 (m, 1H), 7.20 - 7.17 (m, 2H), 6.63 (br s, 1H), 6.30 (s, 1H), 5.27 - 5.22 (m, 1H), 4.49 (s, 2H), 4.20 (s, 3H), 3.44 (s, 3H), 3.20 - 3.11 (m, 1H), 2.66 - 2.58 (m, 1H), 2.17 - 2.07 (m, 2H), 2.04 (br s, 1H), 2.02 - 1.88 (m, 3H), 1.65 (s, 9H).

1-(4-((2,2,2-trifluoroacetoxy)methyl)cyclohexyl)-1H-pyrazole-4-carboxylic acid (Intermediate Q)

Step 1 - tert-butyl 1-(4-(ethoxycarbonyl)cyclohex-1-en-1-yl)-1H-pyrazole-4-carboxylate. To a solution of tert-butyl 1H-pyrazole-4-carboxylate (900 mg, 5.3 mmol, CAS# 611239-23-7) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.57 mmol, CAS# 1049004-32-1) in pyridine (10 mL) was added Cu(OAc) ₂ (1.30 g, 7.14 mmol) at 20°C under nitrogen atmosphere. The reaction was then stirred at 100°C for 10 hours. Upon completion, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (2 x 10 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 100:1 to 100:7) to give the title compound (0.8 g, 69% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 -d) δ = 7.99 (s, 1H), 7.90 (s, 1H), 6.29 - 6.28 (m, 1H), 6.29 - 6.17 (m, 1H), 4.24 - 4.12 (m, 2H), 2.81 - 2.31 (m, 5H), 2.28 - 2.17 (m, 1H), 2.11 - 1.86 (m, 1H), 1.56 (s, 8H), 1.29 (t, J = 7.2 Hz, 3H).

Step 2 - tert-butyl 1-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-1H-pyrazole-4-carboxylate. To a solution of tert-butyl 1-(4-ethoxycarbonylcyclohexen-1-yl)pyrazole-4-carboxylate (750 mg, 2.3 mmol) in THF (17 mL) was added DIBAL-H (1 M, 4.68 mL) at -20°C under nitrogen atmosphere. The reaction was then stirred at -20°C under nitrogen atmosphere for 0.5 h. Upon completion, the reaction was quenched with 5 mL of methanol and then stirred at 0°C for 30 min. The reaction was then dried over sodium sulfate, filtered, and the filtrate was concentrated to provide a residue. The title compound (0.6 g, 92% yield) was obtained as a yellow oil. ^1H NMR (400 MHz, _CDCl3 -d) δ = 7.99 (s, 1H), 7.90 (s, 1H), 6.30 - 6.12 (m, 1H), 3.68 - 3.55 (m, 2H), 2.77 - 2.63 (m, 1H), 2.61 - 2.47 (m, 1H), 2.43 - 2.32 (m, 1H), 2.14 - 1.84 (m, 4H), 1.56 (s, 10H).

Step 3 - tert-butyl 1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxylate. To a solution of Pd/C (1.90 g, 1.80 mmol, 10 wt%) in MeOH (20 mL) was added tert-butyl 1-[4-(hydroxymethyl)cyclohexen-1-yl]pyrazole-4-carboxylate (0.5 g, 1.8 mmol) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 several times. The mixture was stirred under _H2 (15 psi) at 20 °C for 10 h. Upon completion, the reaction was filtered to obtain the filtrate and concentrated to give the title compound (0.55 g) as a colorless oil. LC-MS (ESI ⁺ ) m/z 281.2 (M+H) ⁺ .

Step 4 - 1-(4-((2,2,2-trifluoroacetoxy)methyl)cyclohexyl)-1H-pyrazole-4-carboxylic acid. To a solution of tert-butyl 1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-carboxylate (0.55 g, 1.96 mmol) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol) at 0° C. under nitrogen atmosphere. The reaction was then stirred at 20° C. under nitrogen atmosphere for 4 hours. Upon completion, the reaction was poured into ice water (10 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers are washed with brine (2×10 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give the title compound (0.6 g) as a white solid. LC-MS (ESI ⁺ ) m/z 321.0 (M+H) ⁺ .

(1R,3S)-3-(1-(tert-butyl)-5-(1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate R)

Step 1 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of N-isopropylcarbamate [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (288 mg, 936 umol, intermediate U) and 1-[4-[(2,2,2-trifluoroacetyl)oxymethyl]cyclohexyl]pyrazole-4-carboxylic acid (300 mg, 936 umol, intermediate Q) in ACN (6 mL) was added _T3P (1.8 g, 2.8 mmol, 50% solution in DMF) and DIEA (605.3 mg, 4.6 mmol) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase was washed with brine (2×10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue that was purified by prep-TLC (petroleum ether:ethyl acetate=0:1) to give the title compound (60 mg, 10% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 515.3 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of N-isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[[1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-carbonyl]amino]pyrazol-3-yl]cyclopentyl] (60.0 mg, 116.5 umol) and TEA (35.4 mg, 349.7 umol) in DCM (0.6 mL) was added slowly dropwise a solution of MsCl (110 mg, 960.27 umol) in DCM (0.6 mL) at 0 °C under a stream of nitrogen. The reaction was then stirred at 0° C. under nitrogen atmosphere for 2 hours. Upon completion, the reaction was poured into saturated aqueous sodium bicarbonate (2 mL) at 0° C. and extracted with dichloromethane (2×3 mL). The combined organic phase was washed with brine (2×2 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound (60.0 mg) as a colorless oil. LC-MS (ESI ⁺ ) m/z 593.3 (M+H) ⁺ .

3-(3-Methyl-4-((4-(methylamino)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate S)

This intermediate was synthesized as previously described in WO 2020/264499, WO 2020/264490, WO 2020/113233 and US 2019/192668.

2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid (Intermediate T)

Step 1 - [4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexyl] 4-methylbenzenesulfonate. To a solution of 4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexanol (1 g, 2.71 mmol) and TosCl (517 mg, 2.71 mmol) was added pyridine (10 mL) at 0°C. The mixture was stirred at 0-20°C for 12 hours. Then, the mixture was stirred at 40°C for 12 hours. Upon completion, the mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers are washed with brine (2 x 10 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 8/1) to give the title compound (1 g, 70% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.78 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 1.6, 7.5 Hz, 4H), 7.49 - 7.40 (m, 8H), 4.70 (br s, 1H), 3.46 (d, J = 5.8 Hz, 2H), 2.41 (s, 3H), 1.74 - 1.62 (m, 2H), 1.58 - 1.44 (m, 5H), 1.33 - 1.12 (m, 2H), 1.00 - 0.95 (m, 9H).

Step 2 - 2-[1-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]tert-butyl acetate. To a solution of 2-(1H-pyrazol-4-yl)tert-butyl acetate (300 mg, 1.65 mmol, intermediate AT) and [4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl] 4-methylbenzenesulfonate (1.72 g, 3.29 mmol) in DMSO (17 mL) was added KI (27.3 mg, 164 umol) and KOH (277 mg, 4.94 mmol) at 20 °C. The mixture was stirred at 50 °C for 0.5 h. Upon completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-10% ethyl acetate/petroleum ether at 80 mL/min) to give the title compound (180 mg, 20% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.65 - 7.57 (m, 5H), 7.49 - 7.42 (m, 6H), 7.29 (s, 1H), 5.64 (d, J = 1.8 Hz, 6H), 4.42 (t, J = 5.32 Hz, 3H), 3.70 - 3.46 (m, 2H), 3.36 (s, 2H), 1.80 - 1.51 (m, 17H), 1.45 - 1.38 (m, 9H), 1.03 - 0.99 (m, 9H).

Step 3 - 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid ^. To a solution of tert-butyl 2-[1-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetate (180 mg, 337 umol) in THF (1.5 mL) and H ₂ O (0.5 mL) was added LiOH.H ₂ O (70.8 mg, 1.69 mmol). The mixture was then stirred at 20° C. for 12 h. Upon completion, the mixture was poured into ice water (3 mL) and extracted with ethyl acetate (2×3 mL). The combined organic phase was washed with brine (2×3 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, elution with a gradient of 0-25% ethyl acetate/petroleum ether at 50 mL/min) to afford the title compound (50 mg, 31% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.30 - 12.09 (m, 1H), 7.65 - 7.59 (m, 4H), 7.58 - 7.54 (m, 1H), 7.50 - 7.40 (m, 6H), 7.29 (s, 1H), 3.63 - 3.46 (m, 2H), 3.37 (s, 2H), 2.05 - 1.97 (m, 3H), 1.87 (br d, J = 12.0 Hz, 1H), 1.78 - 1.64 (m, 3H), 1.62 - 1.53 (m, 2H), 1.20 - 1.15 (m, 2H), 1.05 - 0.95 (m, 9H).

(1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate U)

Step 1 - (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate. A solution of (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (300 mg, 839 umol, Intermediate AG) and (4-nitrophenyl) carbonochloridate (254 mg, 1.26 mmol) in anhydrous DCM (5 mL) was treated with pyridine (199 mg, 2.52 mmol, 203 uL) and DMAP (10.3 mg, 83.9 umol) and the reaction mixture was stirred at 20° C. for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, ethyl acetate/petroleum: 0-30%) to afford the title compound (223 mg, 50% yield) as a yellow oil. LC-MS(ESI ⁺ )m/z 523.1(M+H) ⁺ , ^1H NMR (400 MHz, _CDCl3 ) δ = 8.31 - 8.24 (m, 2H), 7.42 - 7.34 (m, 7H), 6.32 - 6.21 (m, 1H), 6.16 (s, 1H), 5.30 - 5.23 (m, 1H), 5.21 (s, 2H), 3.22 - 3.09 (m, 1H), 2.68 - 2.57 (m, 1H), 2.19 - 2.09 (m, 1H), 2.09 - 2.06 (m, 1H), 2.04 - 1.95 (m, 3H), 1.94 - 1.86 (m, 1H), 1.60 (s, 9H).

Step 2 - (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isobutyrate. A solution of [(1R,3S)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl] (4-nitrophenyl) carbonate (220 mg, 421 umol), propan-2-amine (32.4 mg, 547 umol, 47.0 uL) and DIPEA (272 mg, 2.11 mmol, 367 uL) in THF (3 mL) was stirred at 20°C for 4 h. Upon completion, the reaction mixture was diluted with EA (40 mL) and stirred for 5 min. The organic phase was washed with aq. Washing with NaOH (25 mL x 4, 1 M), brine (30 mL), drying over _{anhydrous Na2SO4} , filtering and concentrating in vacuo afforded the title compound (150 mg) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.38 (m, 5H), 6.38 - 5.99 (m, 2H), 5.21 - 5.19 (m, 2H), 5.15 (m, 1H), 4.55 (br s, 1H), 3.89 - 3.65 (m, 1H), 3.14 - 3.00 (m, 1H), 2.51 - 2.39 (m, 1H), 2.04 - 1.99 (m, 1H), 1.97 - 1.75 (m, 5H), 1.58 (s, 9H), 1.20 - 1.07 (m, 6H).

Step 3 - (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isobutyrate (150 mg, 339 umol) in THF (2 mL) and EtOAc (4 mL) was added Pd/C (20 mg, 10 wt%) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 several times. The mixture was stirred under a hydrogen balloon (15 psi) at 20 °C for 4 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide a residue. The residue was purified by flash silica gel chromatography (4 g SepaFlash® silica flash column, ethyl acetate/petroleum: 0-40%) to give the title compound (75 mg, 236 umol, 70% yield) as a yellow oil: LC-MS (ESI ⁺ ) m/z 309.1 (M+H) ⁺ .

[4-[4-[2-[[2-tert-butyl-5-[(1S,3R)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]amino]-2-oxo-ethyl]pyrazol-1-yl]cyclohexyl]methyl methanesulfonate (Intermediate V)

Step 1 - N-Isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]. To a solution of [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] N-isopropylcarbamate (64.7 mg, 209 umol, intermediate U) and 2-[1-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetic acid (100 mg, 209 umol, intermediate T) in pyridine (1 mL) was added EDCI (120 mg, 629 umol) and DMAP (2.56 mg, 20.9 umol) at 20° C. The mixture was stirred at 50° C. for 12 h. Upon completion, the reaction was poured into ice water (2 mL) and extracted with ethyl acetate (2×2 mL). The combined organic phase was washed with brine (2×2 mL), dried over sodium sulfate, then filtered and concentrated to give a residue. The residue was purified by prep-TLC (SiO ₂ , EA:PE=4:1) to give the title compound (100 mg, yield 62%) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.41 (s, 1H), 7.63 - 7.60 (m, 5H), 7.47 - 7.44 (m, 5H), 7.33 (s, 1H), 6.91 (br d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 5.01 - 4.91 (m, 1H), 4.13 - 3.98 (m, 3H), 3.55 - 3.47 (m, 2H), 3.44 - 3.41 (m, 2H), 3.17 (d, J = 5.12 Hz, 1H), 2.34 - 2.32 (m, 1H), 1.95 - 1.77 (m, 6H), 1.73 - 1.57 (m, 8H), 1.26 - 1.14 (m, 6H), 1.04 - 1.00 (m, 18H).

Step 2 - N-isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[[2-[1-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetyl]amino]pyrazol-3-yl]cyclopentyl]. To a solution of N-isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[[2-[1-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetyl]amino]pyrazol-3-yl]cyclopentyl] (100 mg, 130 umol) was added TBAF (1 mL, 1M in THF). The mixture was stirred at 20° C. for 1 hour. Upon completion, the mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiO ₂ , EA:PE=8:1) to give the title compound (47 mg, 51% yield) as a yellow oil: LC-MS (ESI ⁺ ) m/z 529.3 (M+H) ⁺ .

Step 3 - [4-[4-[2-[[2-tert-butyl-5-[(1S,3R)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]amino]-2-oxo-ethyl]pyrazol-1-yl]cyclohexyl]methyl methanesulfonate. To a solution of N-isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[[2-[1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]acetyl]amino]pyrazol-3-yl]cyclopentyl] (35 mg, 66.2 umol) and TEA (13.4 mg, 132 umol) in DCM (0.5 mL) was added MsCl (9.10 mg, 79.4 umol) dropwise slowly at 0 °C and the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched with NaHCO ₃ (sat aq, 1 mL) at 0° C. and extracted with DCM (2×2 mL). The combined organic phase was washed with brine (2×2 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give the title compound (30 mg) as a yellow oil. LC-MS (ESI ⁺ ) m/z 607.2 (M+H) ⁺ .

2-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-3-carboxylic acid (Intermediate W)

Step 1 - 2-(2-prop-2-ynoxyethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-prop-2-ynoxyethoxy)ethanol (6 g, 41.6 mmol, CAS#7218-43-1) and 4-methylbenzenesulfonyl chloride (15.9 g, 83.2 mmol) in DCM (120 mL) was added TEA (21.1 g, 208 mmol) and DMAP (508 mg, 4.16 mmol). The mixture was then stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (120 mL) at 25 °C and then extracted with EtOAc (120 mL × 3). The combined organic layers were washed with EtOAc (120 mL × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) to give the title compound (10.9 g, 30.3 mmol, 73% yield) as an orange oil. LCMS: tR=0.546 min, (ES+) m/z (M+H)+=254.3.

Step 2 - 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate and 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole- ₃ -carboxylate. To a solution of 2-(2-prop-2-ynoxyethoxy)ethyl 4-methylbenzenesulfonate (5.5 g, 18.4 mmol) and methyl 1H-pyrazole-5-carboxylate (2.79 g, 22.1 mmol) in DMF (55 mL) was added _Cs2CO3 (12.0 g, 36.8 mmol) and KI (306 mg, 1.84 mmol). The mixture was stirred at 70°C for 1 h. Upon completion, the reaction mixture was quenched with _H2O (60 mL) at 25°C and then extracted with EtOAc (60 mL x 3). The combined organic layers were washed with EtOAc (60 mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a _residue . The residue was purified by prep-HPLC (column: YMC Triart C18 250 x 50 mm x 7 um; mobile phase: [water ( ₁₀ mM _NH4HCO3 )-ACN]; B%: 16%-46%, 17 min) to give methyl 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (1 g, 22% yield) as an orange solid ( ^1H NMR (400 MHz, DMSO-d6) δ = 7.58 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.66 (t, J = 5.6 Hz, 2H), 4.07 (d, J = 2.4 Hz, 2H), 3.82 (s, 3H), 3.73 (t, J = 5.6 Hz, 2H), 3.47 (s, 4H), 3.40 (t, J = 2.4 Hz, 1H), and 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate (1 g, 3.96 mmol, 22% yield) as an orange solid ( ^1H NMR (400 MHz, DMSO-d6) δ = 7.85 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.35 (t, J = 5.4 Hz, 2H), 4.10 (d, J = 2.4 Hz, 2H), 3.83 - 3.76 (m, 5H), 3.56 - 3.49 (m, 4H), 3.41 (t, J = 2.4 Hz, 1H) were obtained.

Step 3 - 2-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-3-carboxylic acid. To a solution of methyl 2-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-3-carboxylate (1 g, 3.96 mmol) in THF (10 mL) and H ₂ O (2 mL) was added LiOH.H ₂ O (665 mg, 15.8 mmol). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (12 mL) at 25 °C and adjusted to pH < 5 with HCl (1 M), then the solution was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (850 mg, 77% yield) as a white solid. LCMS: tR = 0.337 min, (ES+) m/z (M+H) ⁺ = 239.0.

N-Isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[[2-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] (Intermediate X)

To a solution of 2-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-3-carboxylic acid (840 mg, 3.53 mmol, intermediate W) and N-isopropylcarbamate [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (1.20 g, 3.88 mmol, intermediate U) in MeCN (10 mL) was added T ₃ P (6.73 g, 50% solution in DMF) and DIEA (2.28 g, 17.6 mmol). The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25° C. and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine ( ₁₀ mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 3/1 to 1/1) to give the title compound (1 g, 53% yield) as an orange solid. LCMS: tR = 0.652 min, (ES ⁺ ) m/z (M+H) ⁺ = 529.2.

1-Undec-10-ynylpyrazole-4-carboxylic acid (Intermediate Y)

Step 1 - Undec-10-ynyl 4-methylbenzenesulfonate. To a solution of undec-10-yn-1-ol (2 g, 11.89 mmol) and TosCl (2.72 g, 14.3 mmol) in DCM (20 mL) was added TEA (3.61 g, 35.7 mmol) at 0 °C. The mixture was then stirred at 20 °C for 12 h. Upon completion, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over sodium sulfate, filtered, and then the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-5% ethyl acetate/petroleum ether at 100 mL/min) to afford the title compound (3.27 g, 85% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 2.6 Hz, 1H), 2.42 (s, 3H), 2.12 (dt, J = 2.4, 6.8 Hz, 2H), 1.57 - 1.49 (m, 2H), 1.45 - 1.36 (m, 2H), 1.33 - 1.25 (m, 2H), 1.16 (br d, J = 4.4 Hz, 8H).

Step 2 - 1-Undec-10-ynylpyrazole-4-carboxylic acid. To a solution of undec-10-ynyl 4-methylbenzenesulfonate (3 g, 9.30 mmol) and methyl 1H-pyrazole-4-carboxylate (1.41 g, 11.2 mmol) in DMF (30 mL) was added NaOH (1.12 g, 27.9 mmol) and NaI (139 mg, 930 umol). The mixture was then stirred at 50°C for 2 hours. Upon completion, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The mixture was then adjusted to pH = 6 with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-30% ethyl acetate/petroleum ether at 80 mL/min) to afford the title compound (1.6 g, 65% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.39 - 12.11 (m, 1H), 8.24 (s, 1H), 7.78 (s, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.74 (s, 1H), 2.13 (dt, J = 2.4, 6.8 Hz, 2H), 1.80 - 1.70 (m, 2H), 1.47 - 1.37 (m, 2H), 1.34 - 1.14 (m, 10H).

N-isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[(1-undec-10-ynylpyrazole-4-carbonyl)amino]pyrazol-3-yl]cyclopentyl] (Intermediate Z)

To a solution of 1-undec-10-ynylpyrazole-4-carboxylic acid (600 mg, 2.29 mmol, intermediate Y) and N-isopropylcarbamate [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (588 mg, 1.91 mmol, intermediate U) in MeCN (6 mL) was added _T3P (3.64 g, 5.72 mmol, 50% solution in DMF) and DIEA (1.23 g, 9.53 mmol, 1.66 mL). The mixture was stirred at 60° C. for 12 hours. Upon completion, the mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a gradient of 0-45% ethyl acetate/petroleum ether at 80 mL/min) to afford the title compound (530 mg, 41% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 553.4 (M+H) ⁺ .

1-(Nona-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid (Intermediate AA)

Step 1 - Nona-8-yn-1-yl 4-methylbenzenesulfonate. To a solution of nona-8-yn-1-ol (5 g, 35.6 mmol, CAS#10160-28-8) and 4-methylbenzenesulfonyl chloride (8.16 g, 42.7 mmol) in DCM (60 mL) was added TEA (10.8 g, 106 mmol) at 0 °C. The mixture was then stirred at 0-20 °C for 12 h. Upon completion, the mixture was quenched with sat. NaHCO ₃ (80 mL) and diluted with DCM (60 mL). The organic layer was washed with H ₂ O (60 x 3 mL) and brine (60 x 3 mL), then dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 10/1) to give the title compound (6.8 g, yield 62%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.77 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H), 2.13 (dt, J = 2.4, 7.2 Hz, 2H), 1.92 (t, J = 2.4 Hz, 1H), 1.66 - 1.58 (m, 2H), 1.51 - 1.40 (m, 2H), 1.36 - 1.19 (m, 6H).

Step 2 - 2-(non-8-yn-1-yl)-1H-pyrazole-5-methyl carboxylate. Sodium hydride (978 mg, 28.5 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of 1H-pyrazole-5-methyl carboxylate (1.29 g, 10.1 mmol) in DMF (40 mL) at 0 °C, then the mixture was stirred at 0 °C for 0.5 h. Then a solution of non-8-ynyl 4-methylbenzenesulfonate (3 g, 10.19 mmol) was added dropwise. The resulting mixture was stirred at 0-20 °C for 12 h. The mixture was quenched with sat. NH ₄ Cl (40 mL) and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over Na ₂ SO ₄ , and concentrated in vacuum. The residue was purified by prep-HPLC (FA condition, column: Phenomenex luna C18 250 x 50 mm x 15 um; mobile phase: [water (0.225% FA)-ACN]; B%: 39% to 69%, 25 min) to give the title compound (0.5 g, 19% yield) as a colorless oil ( ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.48 (d, J = 2.0 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 4.62 - 4.52 (m, 2H), 3.89 (s, 3H), 2.18 (dt, J = 2.4, 7.2 Hz, 2H), 1.94 (t, J = 2.4 Hz, 1H), 1.84 (quin, J = 7.2 Hz, 2H), 1.57 - 1.48 (m, 2H), 1.43 - 1.29 (m, 7H)), and methyl 1-non-8-ynylpyrazole-3-carboxylate (1.3 g, 50% yield) as a brown oil ( ¹ H NMR (400 MHz, chloroform-d) δ = 7.40 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 4.19 (t, J = 7.2 Hz, 2H), 3.93 (s, 3H), 2.17 (dt, J = 2.4, 7.2 Hz, 2H), 1.96 - 1.85 (m, 3H), 1.56 - 1.46 (m, 2H), 1.42 - 1.29 (m, 6H)).

Step 3 - 1-(Nona-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid. To a solution of methyl 2-(nona-8-yn-1-yl)-1H-pyrazole-5-carboxylate (0.5 g, 2.01 mmol) in THF (4 mL) was added a solution of LiOH.H ₂ O (337 mg, 8.05 mmol) in H ₂ O (1 mL). The mixture was stirred at 25 °C for 12 h. Upon completion, the solution was diluted with water (10 mL) and extracted with EtOAc (15 mL). The aqueous phase was adjusted to pH < 4 with HCl (1M) and then extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (0.33 g, 63% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.54 (s, 1H), 6.98 (s, 1H), 4.59 (t, J = 7.2 Hz, 2H), 2.18 (dt, J = 2.4, 7.2 Hz, 2H), 1.96 - 1.82 (m, 4H), 1.52 (td, J = 7.2, 14.4 Hz, 3H), 1.45 - 1.31 (m, 8H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(nona-8-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate AB)

A solution of 1-(nona-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid (0.3 g, 1.28 mmol, intermediate AA), N-isopropylcarbamate [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (434 mg, 1.41 mmol, intermediate U), T ₃ P (2.44 g, 3.84 mmol, 50% solution in DMF) and DIEA (330 mg, 2.56 mmol) in MeCN (4 mL) was stirred at 80° C. for 12 h. Upon completion, the mixture was diluted with EtOAc (10 mL) and quenched with sat. NH ₄ Cl (10 mL). The mixture was extracted with EtOAc (20 mL×3) and the organic layer was washed with brine (20 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (0.3 g, yield 36%) as a brown solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.55 (d, J = 2.0 Hz, 1H), 7.47 (br s, 1H), 6.61 (br s, 1H), 6.30 (s, 1H), 5.16 (br s, 1H), 4.60 (t, J = 7.3 Hz, 2H), 3.87 - 3.77 (m, 1H), 3.17 - 3.05 (m, 1H), 2.53 - 2.42 (m, 1H), 2.17 (dt, J = 2.4, 7.2 Hz, 2H), 2.07 - 2.04 (m, 1H), 1.94 - 1.84 (m, 6H), 1.65 (s, 9H), 1.53 - 1.48 (m, 2H), 1.44 - 1.30 (m, 7H), 1.27 (t, J = 7.2 Hz, 1H), 1.15 (dd, J = 2.4, 6.4 Hz, 6H).

1-(dodec-11-yn-1-yl)-1H-pyrazole-3-carboxylic acid (Intermediate AC)

To a solution of 1-dodec-11-ynylpyrazole-3-methyl carboxylate (1.1 g, 3.79 mmol, intermediate AK) and LiOH.H ₂ O (635 mg, 15.1 mmol) in THF (12 mL) and H ₂ O (3 mL) was then stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with 20 mL of H ₂ O at 20° C., then diluted with 10 mL of EtOAc and extracted with 3 mL of EtOAc (20 mL×3). The aqueous phase was then adjusted to pH=3-4, then extracted with 3 mL of EtOAc (20 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (1 g) as a yellow solid. The product was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z 567.7 (M+H) ⁺ .

N-isopropylcarbamate [(1R,3S)-3-[1-tert-butyl-5-[(1-dodec-11-ynylpyrazole-3-carbonyl)amino]pyrazol-3-yl]cyclopentyl] (Intermediate AD)

To a solution of 1-dodec-11-ynylpyrazole-3-carboxylic acid (200 mg, 723 umol, intermediate AC) and (1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl N-isopropylcarbamate (267 mg, 868 umol, intermediate U) in MeCN (2 mL) was added T ₃ P (1.38 g, 2.17 mmol, 50% solution in DMF) and DIEA (467.64 mg, 3.62 mmol). The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (3 mL) at 25° C., then diluted with EtOAc (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with sat. NaCl (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (250 mg, 61% yield) as an orange solid. LCMS: tR=0.840 min, (ES+) m/z (M+H)+=568.1.

1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (Intermediate AE)

Step 1 - 2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-prop-2-ynoxyethoxy)ethanol (2 g, 13.8 mmol) in DCM (60 mL) was added TEA (7.02 g, 69.36 mmol) and DMAP (169 mg, 1.39 mmol) and 4-methylbenzenesulfonyl chloride (5.29 g, 27.7 mmol) at 20 °C under nitrogen atmosphere. The reaction was then stirred at 20 °C under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (60 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with brine (2 x 40 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (3 g, 72% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.82 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.24 - 4.13 (m, 4H), 3.75 - 3.69 (m, 2H), 3.68 - 3.60 (m, 4H), 2.49 - 2.43 (m, 4H).

Step 2 - 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-methylcarboxylate. To a solution of methyl 1H-pyrazole-4-carboxylate (1.0 g, 8.0 mmol) and 2-(2-prop-2-ynoxyethoxy)ethyl 4-methylbenzenesulfonate (2 g, 6.7 mmol) in DMF (40 mL) was added _KI (111 mg, 670 umol) and _Cs2CO3 (4.3 g, 13.4 mmol) at 0°C under nitrogen flow. The reaction was then stirred at 70°C under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to provide a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 100:1 to 100:40) to give the title compound (1.5 g, 88% yield) as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.02 (s, 1H), 7.90 (s, 1H), 4.31 (t, J = 5.12 Hz, 2H), 4.17 (d, J = 2.0 Hz, 2H), 3.86 - 3.84 (m, 2H), 3.82 (s, 3H), 3.67 - 3.63 (m, 2H), 3.62 - 3.57 (m, 2H), 2.45 (t, J = 2.12 Hz, 1H).

Step 3 - 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid. To a solution of 1-[2-(2-prop-2-ynoxyethoxy)ethyl]methylpyrazole-4-carboxylate (1.5 g, 5.95 mmol) in THF (24 mL) and H ₂ O (6 mL) was added ^LiOH.H ₂ O (998 mg, 23.7 mmol) at 20° C. under a stream of nitrogen. The reaction was then stirred at 40° C. under a nitrogen atmosphere for 15 hours. Upon completion, the reaction was poured into ice water (20 mL) and acidified to pH=3 with 3N hydrochloric acid, then extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give the title compound as a residue. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.03 (s, 1H), 7.90 (s, 1H), 4.28 (t, J = 5.12 Hz, 2H), 4.11 (d, J = 2.4 Hz, 2H), 3.80 (t, J = 5.12 Hz, 2H), 3.62 - 3.50 (m, 4H), 2.38 (t, J = 2.4 Hz, 1H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate AF)

To a solution of 1-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-4-carboxylic acid (668 mg, 2.8 mmol, Intermediate AE) and N-isopropylcarbamate [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (0.4 g, 1.30 mmol, Intermediate U) in ACN (10 mL) was added _T3P (2.68 g, 4.21 mmol, 50% solution in DMF) and DIEA (906 mg, 7.01 mmol, 1.22 mL) at 20° C. under a stream of nitrogen. The reaction was then stirred at 60° C. under a nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (15 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (2×10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue that was purified by prep-TLC (petroleum ether:ethyl acetate=0:1) to give the title compound (0.25 g, 33% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.23 - 7.56 (m, 2H), 6.19 (br s, 1H), 5.15 (br s, 1H), 4.77 - 4.60 (m, 1H), 4.33 (br d, J = 4.2 Hz, 2H), 4.18 (d, J = 2.4 Hz, 1H), 3.87 (br t, J = 4.92 Hz, 2H), 3.83 - 3.72 (m, 1H), 3.69 - 3.53 (m, 3H), 3.26 - 2.99 (m, 1H), 2.52 - 2.45 (m, 1H), 2.44 (t, J = 2.4 Hz, 1H), 2.11 - 2.00 (m, 1H), 1.99 - 1.74 (m, 5H), 1.63 (s, 9H), 1.18 - 1.10 (m, 6H).

(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (intermediate AG) and (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (intermediate AH)

Step 1 - Methyl 3,3-dimethoxycyclopentanecarboxylate. To a solution of 3-oxocyclopentanecarboxylic acid (42 g, 328 mmol, CAS#98-78-2) in MeOH (180 mL) was added trimethoxymethane (174 g, 1.64 mol, 180 mL) and TsOH.H ₂ O (12.5 g, 65.6 mmol). The mixture was stirred at 20 °C for 3 h. Then, Na ₂ CO ₃ (80 g) was added to the mixture and the mixture was stirred at 20 °C for 11 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuum. Water (200 mL) was added to the mixture. The mixture was extracted with EtOAc (200 mL x 3). The organic phase was washed with brine (200 mL x 2), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give the title compound (55.2 g, 89% yield) as a yellow oil.1H ^NMR (400 MHz, _CDCl3 ) δ = 3.72 - 3.62 (m, 3H), 3.23 - 3.15 (m, 6H), 2.93 - 2.79 (m, 1H), 2.15 - 2.01 (m, 2H), 2.00 - 1.84 (m, 3H), 1.83 - 1.75 (m, 1H).

Step 2 - 3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile. A solution of n-BuLi (2.5M, 15.9 mL) was added dropwise to a reactor containing THF (120 mL) at -65°C. Anhydrous MeCN (1.64 g, 39.9 mmol, 2.1 mL) was then added dropwise slow enough to maintain the internal temperature below -65°C. The mixture was stirred at -65°C for an additional 1 hour. A solution of methyl 3,3-dimethoxycyclopentanecarboxylate (5 g, 26.6 mmol) in THF (40 mL) was then added dropwise. After addition, the reaction mixture was stirred at -65°C for 2 hours. Upon completion, the reaction was quenched with water (60 mL), neutralized with saturated aq NH ₄ Cl to pH=9-10, and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with sat. aq NaCl (50 mL x 2), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure to give the title compound (3.9 g, 19.8 mmol, 74% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 3.53 - 3.50 (m, 2H), 3.21 - 3.18 (m, 7H), 2.08 (d, J = 8.4 Hz, 2H), 1.94 - 1.81 (m, 4H).

Step 3 - 2-tert-Butyl-5-(3,3-dimethoxycyclopentyl)pyrazol-3-amine. To a solution of tert-butylhydrazine (2.88 g, 23.1 mmol, HCl) in EtOH (40 mL) was added NaOH (925 mg, 23.1 mmol) at 25° C. After addition, the mixture was stirred at 25° C. for 0.5 h, then 3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile (3.8 g, 19.3 mmol) in EtOH (40 mL) was added dropwise. The resulting mixture was stirred at 75° C. for 15.5 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, ethyl acetate/petroleum: 0-35%) to give the title compound (3.7 g, 72% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.43 (s, 1H), 5.48 - 5.35 (m, 1H), 3.56 - 3.43 (m, 1H), 3.49 (br d, J = 1.2 Hz, 1H), 3.23 (d, J = 4.0 Hz, 6H), 3.19 - 3.09 (m, 1H), 2.27 (m, 1H), 2.01 - 1.93 (m, 1H), 1.88 - 1.69 (m, 4H), 1.61 (s, 9H).

Step 4 - (1-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-yl)benzylcarbamate. To a solution of 2-tert-butyl-5-(3,3-dimethoxycyclopentyl)pyrazol-3-amine (3.7 g, 13.8 mmol) in MeCN (50 mL) was added NaHCO ₃ (3.49 g, 41.5 mmol). After addition, the mixture was stirred at 25° C. for 0.5 h, then CbzCl (3.54 g, 20.8 mmol, 2.95 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 15.5 h. Upon completion, the reaction mixture was quenched with H ₂ O (80 mL) and then diluted with ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, ethyl acetate/petroleum: 0-35%) to give the title compound (1.12 g, 21% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 356.3(M+H) ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ = 7.48 - 7.30 (m, 5H), 6.28 (s, 1H), 6.10 (s, 1H), 5.20 (s, 1H), 3.51 - 3.36 (m, 1H), 2.62 - 2.53 (m, 1H), 2.50 - 2.31 (m, 3H), 2.28 - 2.16 (m, 1H), 2.11 - 2.05 (m, 1H), 1.58 (s, 9H).

Step 5 - Benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl N-[2-tert-butyl-5-(3,3-dimethoxycyclopentyl)pyrazol-3-yl]carbamate (1.12 g, 2.96 mmol) in acetone (10 mL) and H ₂ O (10 mL) was added TosOH (10.3 g, 59.8 mmol) and the mixture was then stirred at 25 °C for 14 h. Upon completion, the mixture was concentrated and diluted with water (5 mL) and EtOAc (5 mL) then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. NaHCO ₃ (500 mL×3) and brine (5 mL×3), and dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (1.1 g) as a yellow solid. LC-MS (ESI ⁺ ) m/z 356.0 (M+H).

Step 6 - (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate. To a solution of (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (1 g, 2.81 mmol) in THF (15 mL) was added LiBHEt ₃ (1 M, 5.63 mL) dropwise at -65 °C under N ₂ . After addition, the mixture was stirred at -65 °C for 2 h. Upon completion, the reaction mixture was quenched with sat. aq NaHCO ₃ (30 mL) at -40 to -30 °C. Next, ydrogen peroxide (aqueous 30%, 5 g) was added dropwise to the mixture while maintaining the internal temperature at −10 to 0° C. The mixture was then stirred at 10° C. for 1 h. Upon completion, the solution was then extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with sat. aq Na ₂ SO ₃ (2×20 mL) and sat. aq NaCl (30 mL). The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, ethyl acetate/dichloromethane: 0-20%) to provide the title compound (708 mg, 68% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.06 (br s, 1H), 7.46 - 7.31 (m, 5H), 5.92 (s, 1H), 5.12 (s, 2H), 4.56 (d, J = 4.4 Hz, 1H), 4.19 - 4.11 (m, 1H), 2.89 (m, 1H), 2.25 - 2.14 (m, 1H), 1.90 - 1.80 (m, 1H), 1.78 - 1.68 (m, 2H), 1.61 - 1.55 (m, 1H), 1.54 - 1.49 (m, 1H), 1.47 (s, 9H).

Step 7 - (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate and (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate. The enantiomers of (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (700 mg, 1.96 mmol) were separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH3H2O MEOH]; B%: 20% to 20%, 2.4; 180 min) to give (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (308 mg, 43% yield) as a white solid (LC-MS(ESI ⁺ )m/z 358.2(M+H) ⁺ SFC (first eluting enantiomer peak, 1.076 min); ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.20 - 8.85 (m, 1H), 7.50 - 7.18 (m, 5H), 5.93 (s, 1H), 5.12 (s, 2H), 4.57 (d, J = 4.0 Hz, 1H), 4.29 - 4.10 (m, 1H), 2.90 (m, 1H), 2.32 - 2.12 (m, 1H), 1.91 - 1.80 (m, 1H), 1.78 - 1.67 (m, 2H), 1.66 - 1.56 (m, 1H), 1.56 - 1.51 (m, 1H), 1.48 (s, 9H) and (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (308 mg, yield 43%) were obtained as a white solid.

3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate AI)

Step 1 - Methyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate. A solution of methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (1 g, 5.88 mmol, CAS# 1208081-25-7) and DIEA (987 mg, 7.64 mmol, 1.33 mL) in DCM (12 mL) was cooled to 0°C. A solution of MsCl (1.08 g, 9.43 mmol, 730 uL) in DCM (3 mL) was then added dropwise. The mixture was stirred at 0°C for 45 minutes and then at 20°C for 1 hour 15 minutes. Upon completion, the reaction mixture was quenched with sat. _NH4Cl (30 mL) and then extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1.46 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.96 (s, 1 H) 5.24 (s, 2 H) 4.19 (s, 3 H) 3.90 (s, 3 H) 3.01 (s, 3 H).

Step 2 - Methyl 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylate. To a solution of 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate (1.46 g, 5.88 mmol) in MeOH (15 mL) was added NaOMe (635 mg, 11.8 mmol) at 20°C. The mixture was stirred at 70°C for 30 min. Upon completion, the reaction mixture was poured into 0.5N HCl (30 mL) with stirring. The pH of the mixture was adjusted to 8 with sodium bicarbonate, then extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to give the product. The crude product was purified by silica gel column chromatography (PE/EA=50/1-8/1) to give the title compound (750 mg, 69% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ ppm 6.82 (s, 1H) 4.34 (s, 2H) 4.06 (s, 3H) 3.83 (s, 3H) 3.25 (s, 3H).

Step 3 - 3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid. To a solution of methyl 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (740 mg, 4.02 mmol) in THF (7.6 mL) was added water (2.5 mL) and lithium hydroxide monohydrate (337 mg, 8.04 mmol). The mixture was stirred at 20 °C for 16 h. Upon completion, the pH of the reaction mixture was adjusted to 3-4 with aq. HCl (1 M), then diluted with 25 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (423 mg, 62% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.23 - 3.26 (m, 3H) 4.04 (s, 3H) 4.32 (s, 2H) 6.75 (s, 1H) 13.12 - 13.51 (m, 1H).

Methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylate (Intermediate AJ) and Methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-3-carboxylate (Intermediate AK)

Step 1 - Dodec-11-yn-1-yl 4-methylbenzenesulfonate. To a solution of dodec-11-yn-1-ol (3 g, 16.5 mmol, CAS#18202-10-3) and 4-methylbenzenesulfonyl chloride (3.45 g, 18.1 mmol, CAS#98-59-9) in DCM (30 mL) was added TEA (5.00 g, 49.4 mmol) at 0 °C, then the mixture was stirred at 0-20 °C for 12 h. Upon completion, the reaction mixture was quenched by addition of 50 mL of NH ₄ Cl at 20 °C, then diluted with 20 mL of EtOAc and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 3/1) to give the title compound (3.6 g, yield 65%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 7.78 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 2.8 Hz, 1H), 2.42 (s, 3H), 2.13 (dt, J = 2.4, 6.8 Hz, 2H), 1.53 (quin, J = 6.8 Hz, 2H), 1.46 - 1.37 (m, 2H), 1.36 - 1.27 (m, 2H), 1.24 - 1.13 (m, 10H).

Step 2 - Methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylate and Methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-3-carboxylate. To a solution of methyl 1H-pyrazole-5-carboxylate (1.19 g, 9.45 mmol, CAS#15366-34-4) and dodec-11-ynyl 4-methylbenzenesulfonate (2.65 g, 7.88 mmol) in DMF (30 mL) was added KI (131 mg, 788 umol) and _Cs2CO3 ( _5.13 g, 15.8 mmol) and the mixture was then stirred at 70°C for 1 h. Upon completion, the reaction mixture was quenched with _H2O (30 mL) at 20°C, then diluted with 30 mL of EtOAc and extracted with 30 mL of EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylate (1 g, 43.7% yield) as a white solid ( ₁ H NMR (400 MHz, DMSO-d6) δ = 7.55 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.47 (t, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.72 (t, J = 2.8 Hz, 1H), 2.13 (dt, J = 2.4, 6.8 Hz, 2H), 1.72 (quin, J = 7.2 Hz, 2H), 1.47 - 1.37 (m, 2H), 1.36 - 1.29 (m, 2H), 1.22 (br s, 10H), and methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-3-carboxylate (1.1 g, 48% yield) were obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.55 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.47 (t, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.72 (t, J = 2.8 Hz, 1H), 2.13 (dt, J = 2.8, 6.8 Hz, 2H), 1.72 (q, J = 7.1 Hz, 2H), 1.47 - 1.37 (m, 2H), 1.36 - 1.29 (m, 2H), 1.22 (br s, 10H).

1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid ((Intermediate AL)

To a solution of methyl 2-dodec-11-ynylpyrazole-3-carboxylate (1 g, 3.44 mmol, intermediate AJ) and LiOH.H ₂ O (578 mg, 13.8 mmol) in THF (12 mL) and H ₂ O (4 mL) was then stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with 20 mL of H ₂ O at 20° C., then diluted with 10 mL of EtOAc and extracted with 3 mL of EtOAc (20 mL×3). The aqueous phase was then adjusted to pH=3-4, then extracted with 3 mL of EtOAc (20 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (930 mg) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 13.95 - 11.71 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.47 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 2.4 Hz, 1H), 2.12 (dt, J = 2.4, 6.8 Hz, 2H), 1.91 (s, 2H), 1.72 (quin, J = 7.2 Hz, 2H), 1.46 - 1.37 (m, 2H), 1.36 - 1.27 (m, 2H), 1.22 (br s, 9H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate AM)

To a solution of 1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid (500 mg, 1.81 mmol, Intermediate AL) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (558 mg, 1.81 mmol, Intermediate U) in MeCN (10 mL) was added DIEA (1.17 g, 9.05 mmol) and _T3P (3.45 g, 5.43 mmol, 50% solution) and the mixture was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was quenched with _H2O (10 mL) at 20° C., then diluted with EtOAc (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine ( ₁₀ mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 1/1) to give the title compound (300 mg, 529 umol, 29% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 567.7 (M+H) ⁺ .

3-[4-(7-aminoheptyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate AN)

Step 1 - Hepta-6-yn-1-yl methanesulfonate. To a stirred solution of hepta-6-yn-1-ol (30.00 g, 267.5 mmol) in DCM (450.00 mL) was added TEA (92.68 mL, 668.6 mmol) and MsCl (45.95 g, 401.1 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was then stirred at room temperature under nitrogen atmosphere for 2 h. Upon completion, the mixture was diluted with water (250 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (50 g). ^1H NMR (400 MHz, _CDCl3 ) δ 4.28-4.24 (m, 2H), 3.03 (s, 3H), 2.27-2.22 (m, 2H), 1.98 (s, 1H), 1.84-1.77 (m, 2H), 1.60-1.52 (m, 6H).

Step 2 - 7-Azidohept-1-yne. To a stirred solution of hepta-6-yn-1-yl methanesulfonate (50.00 g, 262.8 mmol) in DMF (500.0 mL) was added _NaN3 (25.63 g, 394.2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C under nitrogen atmosphere overnight. Upon completion, the reaction mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL) and then dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (36 g) as a pale oil. ^1H NMR (400 MHz, chloroform-d) δ 3.30 (t, J = 6.8 Hz, 2H), 2.23 (td, J = 6.8, 2.6 Hz, 2H), 1.97 (s, 1H), 1.72-1.41 (m, 6H).

Step 3 - Hepta-6-yn-1-amine hydrochloride. To a stirred solution of 7-azidohept-1-yne (36.00 g, 262.4 mmol) in THF (400 mL) and H ₂ O (40.00 mL) was added PPh ₃ (103.24 g, 393.6 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 60° C. under nitrogen atmosphere for 2 h. Upon completion, the solution was concentrated under reduced pressure and diluted with DCM (300 mL). The mixture was acidified to pH 1 with HCl (2 M aq.) and the aqueous layer was extracted with DCM (3×100 mL). The aqueous layer was concentrated under reduced pressure to give the title compound (38 g, 98% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.09 (broad, 3H), 2.82-2.67 (m, 3H), 2.18-2.14 (m, 2H), 1.61-1.53 (m, 2H), 1.49-1.35 (m, 4H). LC/MS (ESI, m/z): [(M + 1)] ⁺ = 112.2.

Step 4: tert-Butyl N-(hept-6-yn-1-yl)carbamate. To a stirred solution of hept-6-yn-1-amine hydrochloride (28.00 g, 190.5 mmol) in DCM (500.00 mL) was added TEA (144.8 mL, 952.4 mmol) and Boc ₂ O (62.28 g, 285.7 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Upon completion, the reaction mixture was diluted with water (1 L) and extracted with CH ₂ Cl ₂ (3×200 mL). The combined organic layers were washed with brine (2×300 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give the title compound (40 g, 99% yield) as a pale yellow solid. ¹ H NMR (400 MHz, chloroform-d) δ 4.56-4.52 (m, 1H), 3.16-3.12 (m, 2H), 2.21 (td, J = 7.0, 2.6 Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H), 1.62-1.49 (m, 6H), 1.46 (s, 9H). LC/MS(ESI, m/z): [(M + 1 - 56)] ⁺ = 156.2.

Step 5 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hept-6-yn-1-yl]carbamate. To a stirred mixture of 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate H) and tert-butyl N-(hept-6-yn-1-yl)carbamate (10.00 g, 47.32 mmol) in DMA (50.00 mL) and TEA (25.00 mL) was added CuI (450.55 mg, 2.366 mmol) and Pd( _PPh3 ) ₄ (2.73 g, 2.34 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. Upon completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse phase flash (Column: Spherical C18, 20-40 um, 330 g; Mobile phase A: Water (0.05% FA), Mobile phase B: ACN; Flow rate: 45 mL/min; Gradient (B%): 5%-5%, 8 min; 40%-70%, 30 min; 70%-95%; 0 min; 95%, 5 min; Detector: 254 nm; Rt: 22.3 min) to give the title compound (6 g, 54% yield) as a pale yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.81 (t, J = 5.9 Hz, 1H), 5.39 (dd, J = 12.6, 5.4 Hz, 1H), 3.65 (s, 3H), 2.99-2.79 (m, 3H), 2.78-2.56 (m, 2H), 2.51-2.47(m, 2H), 2.06-1.98 (m, 1H), 1.56 (d, J = 6.9 Hz, 2H), 1.43-1.39 (m, 4H), 1.36 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 469.3.

Step 6 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]heptyl]carbamate. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hept-6-yn-1-yl]carbamate (6.50 g, 13.9 mmol) in MeOH (500 mL) was added Pd/C (2.21 g, 20.8 mmol) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. Upon completion, the resulting mixture was filtered and the filter cake was washed with MeOH (5 x 100 mL). The filtrate was concentrated under reduced pressure to give the title compound (6 g, 92% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 6.97-6.93 (m, 2H), 6.88-6.85 (m, 1H), 6.77 (t, J = 5.8 Hz, 1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 3.55 (s, 3H), 2.95-2.86 (m, 5H), 2.80-2.57 (m, 2H), 2.04-1.96 (m, 1H), 1.563-1.56 (m, 2H), 1.41-1.22 (m, 17H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 473.3.

Step 7 - 3-(4-(7-aminoheptyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]heptyl]carbamate (6.00 g, 12.9 mmol) in DCM (50.00 mL) was added dropwise HCl (gas) in 1,4-dioxane (20 mL) at room temperature under air atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with Et ₂ O to afford the title compound (4.5 g, 90% yield) as a white solid. ^1H NMR (300 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.85 (broad, 3H), 7.01-6.92 (m, 2H), 6.88-6.84 (m, 1H), 5.38 (dd, J = 12.7, 5.4 Hz, 1H), 3.56 (s, 3H), 2.97- 2.83 (m, 3H), 2.80-2.63 (m, 4H), 2.05-1.91 (m, 1H), 1.64-1.51 (m, 4H), 1.43-1.24 (m, 6H). LC/MS (ESI, m/z): [(M + 1)] ⁺ = 373.3.

3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid (intermediate AO)

Step 1 - hept-6-yn-1-yl 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylate. Sodium hydride (264 mg, 6.61 mmol, 60% dispersion in mineral oil) was added to a solution of hept-6-yn-1-ol (618 mg, 5.51 mmol, CAS# 63478-76-2) in THF (8 mL) at 0 °C and the resulting mixture was stirred at 0 °C for 0.5 h. Then a solution of 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate (800 mg, 2.76 mmol, synthesized by steps 1-2 of intermediate AI) in THF (2 mL) was added and the mixture was stirred at 0 °C for 2 h. Upon completion, the reaction mixture was quenched with 20 mL of H ₂ O at 20° C., then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (600 mg, yield 51.84%) as a brown oil. LC-MS (ESI ⁺ ) m/z 345.2 (M+H) ⁺ .

Step 2 - 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid. To a solution of 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylate hept-6-yn-1-yl (600 mg, 1.74 mmol) in H ₂ O (1 mL) and THF (4 mL) was added ^LiOH.H ₂ O (292 mg, 6.97 mmol) and the mixture was then stirred at 20°C for 3 hours. Upon completion, the reaction mixture was filtered and diluted with H ₂ O (5 mL) and then extracted with EtOAc (8 mL x 3). The aqueous phase was then adjusted to pH = 3-4 and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over _Na2SO4 , filtered and concentrated in vacuo to give the title compound (400 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ₌ ^13.35 - 13.25 (m, 1H), 6.80 - 6.66 (m, 1H), 4.38 - 4.30 (m, 2H), 3.38 (q, J = 6.0 Hz, 3H), 3.29 (br s, 3H), 2.74 - 2.71 (m, 1H), 2.14 (dt, J = 2.4, 6.8 Hz, 4H), 1.44 - 1.34 (m, 9H).

(1R,3S)-3-(1-(tert-butyl)-5-(3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate AP)

To a solution of 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid (243 mg, 973 umol, intermediate AO), isopropylcarbamate ((1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (200 mg, 648 umol, intermediate U) in pyridine (2 mL) was added POCl ₃ (199 mg, 1.3 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Upon completion, the reaction mixture was quenched by addition of 3 mL of glacial NaHCO ₃ at 20° C. and extracted with 1 mL of EtOAc (2 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was analyzed by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate = 0:1) to give the title compound (70 mg, 20% yield) as a yellow solid. ^1H NMR (400 MHz, _CD3Cl ) δ 6.67 - 6.59 (m, 1H), 6.32 (s, 1H), 5.21 - 5.11 (m, 1H), 5.00 (br dd, J = 2.8, 4.4 Hz, 1H), 4.52 (s, 2H), 4.19 (s, 3H), 3.86 - 3.75 (m, 1H), 3.54 (t, J = 6.8 Hz, 2H), 3.21 - 3.12 (m, 1H), 2.93 - 2.84 (m, 2H), 2.56 - 2.42 (m, 2H), 2.21 (dt, J = 2.4, 6.8 Hz, 3H), 2.10 - 2.03 (m, 2H), 1.94 (t, J = 2.4 Hz, 1H), 1.92 - 1.86 (m, 2H), 1.66 (s, 8H), 1.63 - 1.46 (m, 6H), 1.19 - 1.11 (m, 6H).

tert-Butyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate (Intermediate AQ)

Step 1 - 3-ethyl 5-tert-butyl 1-methyl-1H-pyrazole-3,5-dicarboxylate. A solution of ethyl (E)-ethyl 2-(2-methylhydrazono)acetate (10 g, 76.8 mmol, MDL# MFCD31391018), tert-butyl acrylate (14.8 g, 115 mmol), _I2 (3.9 g, 15.4 mmol, CAS# 1663-39-4), and _benzoyl peroxide (55.8 g, 230 mmol) in ACN (180 mL) was stirred at 80 °C for 6 h. Upon completion, the mixture was quenched with _Na2SO3 (200 mL) _and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over _Na2SO4 , and then concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (6.5 g, 33% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ = 7.15 (s, 1H), 4.28 (q, J = 7.2 Hz, 3H), 4.13 (s, 3H), 3.32 (s, 2H), 1.54 (s, 9H), 1.29 (t, J = 7.2 Hz, 4H).

Step 2 - tert-butyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate. To a solution of 3-ethyl 5-tert-butyl 1-methyl-1H-pyrazole-3,5-dicarboxylate (6.5 g, 25.6 mmol) in THF (60 mL) was added LiBH ₄ (3 g, 138 mmol) slowly at 0 °C, and then the mixture was stirred at the same temperature for 1 h. Upon completion, the reaction mixture was quenched by dropwise addition of H ₂ O (60 mL) at 20 °C, and then the solution was extracted with EtOAc mL (60 mL x 3). The combined organic layers were washed with brine (60 mL x 2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 3/1) to give the title compound (2.5 g, 46% yield) as a yellow solid: LC-MS (ESI ⁺ ) m/z 213.3 (M+H) ⁺ .

Step 3 - tert-butyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate. To a solution of tert-butyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (2.4 g, 11.3 mmol) and DIEA (4.39 g, 33.9 mmol) in DCM (30 mL) was added methanesulfonyl chloride (1.94 g, 16.9 mmol) at 0 °C, then the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl (sat. aq, 20 mL) at 20 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (1.5 g, 46% yield) as a yellow gum: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.91 (s, 1H), 5.19 (s, 2H), 4.06 (s, 3H), 3.22 (s, 3H), 1.54 (s, 9H).

1-Methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid (Intermediate AR)

Step 1 - 1-Methyl-3-((nona-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylate non-8-yn-1-yl. Sodium hydride (248 mg, 6.20 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of nona-8-yn-1-ol (724 mg, 5.17 mmol, CAS# 10160-28-8) in THF (8 mL) at 0 °C and then this mixture was stirred at 0 °C for 0.5 h. Next, a solution of 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate tert-butyl (750 mg, 2.58 mmol, Intermediate AQ) in THF (4 mL) was added dropwise and the resulting mixture was stirred at 0 °C for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (600 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 401.3 (M+H) ⁺ .

Step 2 - 1-Methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid. ^LiOH.H ₂ O (251 mg, 5.99 mmol) was added in one portion to a solution of 1-methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylate non-8-yn-1-yl (600 mg, 1.50 mmol) in H ₂ O (2 mL) and THF (8 mL), then the resulting mixture was stirred at 25°C for 12 hours. Upon completion, the reaction mixture was filtered and diluted with H ₂ O (5 mL) and extracted with EtOAc (8 mL x 3). The aqueous phase was then adjusted to pH = 3-4 and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (400 mg) as a brown oil. LC-MS (ESI ⁺ ) m/z 279.1 (M+H) ⁺ .

(1R,3S)-3-(1-(tert-butyl)-5-(1-methyl-3-((nona-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate AS)

POCl ₃ (441 mg, 2.87 mmol) was added dropwise to a solution of 1-methyl-3-((nona-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid (400 mg, 1.44 mmol, Intermediate AR) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (488 mg, 1.58 mmol, Intermediate U) in pyridine (4 mL) at 0° C., then the resulting mixture was stirred at 0° C. for 2 h. Upon completion, the reaction mixture was quenched with ice H ₂ O (5 mL) at 20° C. and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (210 mg, yield 26%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 6.99 (s, 1H), 6.91 (br d, J = 5.6 Hz, 1H), 6.02 (s, 1H), 5.01 - 4.96 (m, 1H), 4.39 (s, 2H), 4.02 (s, 3H), 3.45 - 3.40 (m, 2H), 2.72 (t, J = 2.8 Hz, 1H), 2.39 (br dd, J = 8.0, 14.4 Hz, 2H), 2.13 (dt, J = 2.8, 6.8 Hz, 2H), 1.96 (br d, J = 7.2 Hz, 1H), 1.86 (td, J = 3.2, 5.6 Hz, 1H), 1.74 - 1.67 (m, 2H), 1.56 (s, 1H), 1.51 (s, 9H), 1.43 - 1.27 (m, 8H), 1.03 (s, 3H), 1.01 (s, 3H).

2-(1H-pyrazol-4-yl) tert-butyl acetate (AT)

Step 1 - (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide. Zn (40.6 g, 622 mmol, powder) was added slowly to a solution of HCl (1M, 232 mL). The mixture was stirred at 20°C for 5 min. The mixture was filtered and the solid was washed with acetone (100 mL x 2). The solid was then dried under reduced pressure. A mixture of Zn (27 g) and TMSCl (2.23 g, 20.5 mmol) in dry THF (120 mL) was warmed to 60°C. A solution of 2-bromoacetate tert-butyl (40 g, 205 mmol, CAS#5292-43-3) in THF (270 mL) was then added dropwise to the reaction mixture. The mixture was stirred at 60°C for 0.5 h. The mixture was filtered and the filtrate was used in the next step without further purification.

Step 2 - tert-Butyl 2-(1H-pyrazol-4-yl)acetate. To a mixture of tert-butyl 4-bromopyrazole-1-carboxylate (25 g, 101 mmol), _Pd2 (dba) ₃ (4 g, 4.37 mmol), XPhos (4.5 g, 9.44 mmol) was added a solution of bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (52.7 g, 202 mmol) in THF (380 mL) in one portion under _N2 . The mixture was stirred at 70 °C under _N2 for 12 h. The mixture was concentrated in vacuum and purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 2/1) to give the title compound (5 g, 27.4 mmol, 27% yield). ^1H NMR (400 MHz, _CDCl3 ) δ = 7.57 (s, 2H), 3.47 (s, 2H), 1.48 (s, 9H).

2-(1-(hept-6-yn-1-yl)-1H-pyrazol-4-yl)isopropyl acetate (Intermediate AU)

Step 1: Hepta-6-yn-1-yl 4-methylbenzenesulfonate. To a solution of hepta-6-yn-1-ol (1.00 g, 8.92 mmol, CAS#63478-76-2) and TEA (2.71 g, 26.75 mmol) in DCM (12 mL) was added TosCl (1.87 g, 9.81 mmol) slowly at 0 °C. The mixture was stirred at 20 °C for 2 h. Upon completion, the mixture was diluted with DCM (20 mL), then washed with water (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate=20/1) to give the title compound (2.00 g, 84% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H), 2.15 (dt, _J1 = 6.8 Hz, _J2 = 2.4 Hz, 2H), 1.93 (t, J = 2.4 Hz, 1H), 1.74-1.62 (m, 2H), 1.50-1.38 (m, 4H).

step 2 - 2-(1-(hept-6-yn-1-yl)-1H-pyrazol-4-yl)isopropyl acetate. To a solution of 2-(1H-pyrazol-4-yl)tert-butyl acetate (400 mg, 2.20 mmol, intermediate AT) in DMSO (6 mL) was added KOH (370 mg, 6.59 mmol) and hept-6-ynyl 4-methylbenzenesulfonate (760 mg, 2.85 mmol) in one portion followed by NaI (33 mg, 0.22 mmol). The mixture was stirred at 50 °C for 2 h. Upon completion, the residue was poured into ice water (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over _{anhydrous Na2SO4} , filtered and concentrated in reduced pressure. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate=30/1 to 20/1) to give the title compound (350 mg, 48% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 277.1 (M+H) ⁺ .

2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetic acid (Intermediate AV)

Step 1 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate tert-butyl. To a mixture of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (245 mg, 0.72 mmol, Intermediate H), 2-(1-hept-6-ynylpyrazol-4-yl) _tert -butyl acetate (200 mg, 0.61 mmol, Intermediate AU), Pd( _PPh3 ) _2Cl2 (51 mg, 0.07 mmol) and CuI (14 mg, 0.07 mmol) in DMF (8 mL) was added TEA (110 mg, 1.09 mmol) in one portion. This mixture was stirred at 60 °C under _N2 for 3 h. Upon completion, the mixture was concentrated in vacuo and purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 11.5 min), then lyophilized to give the title compound (40 mg, 10% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 534.3 (M+H) ⁺ .

Step 2 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)tert-butyl acetate. To a solution of 2-[1-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]hept-6-ynyl]pyrazol-4-yl]tert-butyl acetate (40 mg, 0.07 mmol) in THF (3 mL) was added Pd/C (20 mg, 10 wt%) in one portion. The mixture was stirred at 20° C. under H ₂ (15 psi) for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (39 mg, 97% yield) as a colorless oil: LC-MS (ESI ⁺ ) m/z 538.4 (M+H) ⁺ .

Step 3 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetic acid. To a solution of tert-butyl 2-[1-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]heptyl]pyrazol-4-yl]acetate (39 mg, 0.07 mmol) in DCM (1.5 mL) was added TFA (462 mg, 4.05 mmol) slowly at 0°C. The mixture was stirred at 20°C for 3 hours. Upon completion, the mixture was concentrated in vacuo to provide the title compound (34 mg, 97% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 482.3 (M+H) ⁺ .

3-(1-(non-8-yn-1-yl)-1H-pyrazol-4-yl)acetic acid (Intermediate AW)

Step 1 - 2-(1-(nona-8-yn-1-yl)-1H-pyrazol-4-yl)tert-butyl acetate. To a solution of 2-(1H-pyrazol-4-yl)tert-butyl acetate (667 mg, 3.66 mmol, intermediate AT) and non-8-yn-1-yl methanesulfonate (1.2 g, 5.50 mmol, synthesized by step 1 of intermediate O) in DMSO (14 mL) was added KOH (616 mg, 11.0 mmol) and KI (60.8 mg, 366 umol) at 20 °C under nitrogen flow. The reaction was then stirred at 50 °C under nitrogen atmosphere for 10 h. On completion, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic phase was washed with brine (4 x 10 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give a residue. The reaction was purified by column chromatography on silica gel (ethyl acetate = 100:1 to 100:30) to give the title compound (0.8 g, 71.7% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.33 (s, 1H), 7.19 (s, 1H), 4.00 (t, J = 7.1 Hz, 2H), 3.32 (s, 2H), 2.10 (dt, J = 2.6, 7.1 Hz, 2H), 1.87 - 1.84 (m, 1H), 1.78 (td, J = 7.1, 14.2 Hz, 2H), 1.41 - 1.22 (m, 18H).

Step 2 - 3-(1-(nona-8-yn-1-yl)-1H-pyrazol-4-yl)acetic acid. To a solution of 2-(1-(nona-8-yn-1-yl)-1H-pyrazol-4-yl)tert-butyl acetate (400 mg, 1.31 mmol) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol) at 20 °C under nitrogen flow. The reaction was then stirred at 20 °C under nitrogen atmosphere for 1 h. Upon completion, the reaction was poured into ice water (8 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL) and dried over sodium sulfate. The filtrate was then filtered to obtain and concentrated to give the title compound (370 mg) as a colorless oil. ^1H NMR (400 MHz, CDCl3) δ 7.6 (s, 1H), 7.47 (s, 1H), 4.19 (t, J = 7.2 Hz, 2H), 3.59 (s, 2H), 2.21 - 2.15 (m, 2H), 1.98 - 1.92 (m, 1H), 1.87 (quin, J = 7.2 Hz, 2H), 1.46 - 1.30 (m, 8H).

(1R,3S)-3-(1-(tert-butyl)-5-(2-(1-(nona-8-yn-1-yl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate AX)

To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (400 mg, 1.30 mmol, Intermediate U) and 2-(1-(nona-8-yn-1-yl)-1H-pyrazol-4-yl)acetic acid (611 mg, 2.46 mmol, Intermediate AW) in ACN (4 mL) was added _T3P (2.48 g, 3.89 mmol, 50% solution in DMF) and DIEA (838 mg, 6.48 mmol) at 20° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (2×5 mL) and dried over sodium sulfate. The filtrate was then filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (0.5 g, 928 umol, yield 72%) as a colorless oil. ^1H NMR (400 MHz, CDCl3) δ = 7.51 (s, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 6.34 (s, 1H), 5.14 (br s, 1H), 4.64 - 4.51 (m, 1H), 4.13 (tt, J = 3.5, 7.2 Hz, 3H), 3.81 (br d, J = 6.6 Hz, 1H), 3.64 (s, 2H), 3.07 (quin, J = 8.5 Hz, 1H), 2.44 (td, J = 6.9, 13.8 Hz, 1H), 2.24 - 2.13 (m, 2H), 2.05 (s, 1H), 2.04 - 1.98 (m, 1H), 1.94 (t, J = 2.6 Hz, 1H), 1.92 - 1.73 (m, 6H), 1.58 - 1.47 (m, 3H), 1.43 (s, 8H), 1.37 - 1.30 (m, 4H), 1.18 - 1.12 (m, 6H).

2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetic acid (Intermediate AY)

Step 1: 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate tert-butyl. To a mixture of 2-(1-hept-6-ynylpyrazol-4-yl)tert-butyl acetate (100 mg, 0.30 mmol, Intermediate AU), 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6 _- dione (122 mg, 0.36 mmol, Intermediate J), Pd( _PPh3 ) _2Cl2 (25 mg, 0.04 mmol) and CuI (7 mg, 0.04 mmol) in THF (1.5 mL) and ACN (1.5 mL) was added TEA (55 mg, 0.54 mmol) in one portion. The mixture was stirred at 60 °C under _N2 for 3 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 11.5 min) and lyophilized to give the title compound (70 mg, 36% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 534.3 (M+H) ⁺ .

Step 2 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)tert-butyl acetate. To a solution of 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hept-6-yn-1-yl)-1H-pyrazol-4-yl)tert-butyl acetate (70 mg, 0.13 mmol) in THF (3 mL) was added Pd/C (20 mg, 10 wt%) in one portion. The mixture was stirred at 20 °C under _H2 atmosphere (15 psi) for 12 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (70 mg, 99% yield) as a colorless oil: LC-MS (ESI+) m/z 538.4 (M+H) ⁺ .

Step 3 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetic acid. To a solution of 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)tert-butyl acetate (70 mg, 0.13 mmol) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol) slowly at 0 °C. This mixture was stirred at 20 °C for 3 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (62 mg, 99% yield) as a yellow oil: LC-MS (ESI ⁺ ) m/z 482.3 (M+H) ⁺ .

1-(7-bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (Intermediate AZ)

Step 1 - 7-Bromo-3-iodo-imidazo[1,2-a]pyridine. To a solution of 7-bromoimidazo[1,2-a]pyridine (9.50 g, 48.2 mmol, CAS#808744-34-5) in DMF (150 mL) was added NIS (13.02 g, 57.86 mmol) at 25 °C. The mixture was then stirred at ₁₀₀ °C for 1 h. Upon completion, the reaction mixture was poured into 400 mL of water and extracted with EtOAc (200 mL x 2). The organic layer was washed with water (200 mL), saturated brine (200 mL), dried over _Na2SO4 , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, elution with a gradient of 0-5% ethyl acetate/petroleum ether at 150 mL/min) to give the compound (11.6 g, 74% yield) as a brown-black solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.67 (s, 1H), 7.04 (dd, J = 2.0, 7.3 Hz, 1H).

Step 2 - 1-(7-Bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione. To a solution of 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (4.00 g, 17.0 mmol, intermediate CR), and 7-bromo-3-iodo-imidazo[1,2-a]pyridine (6.62 g, 20.4 mmol) in 1,4-dioxane (80.0 mL) was added _Cs2CO3 ( _11.1 g, 34.1 mmol), CuI (650 mg, 3.42 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (485 mg, 3.42 mmol) at 25 °C under _N2 . The mixture was then stirred at 80° C. for 16 hours. Upon completion, the reaction mixture was poured into 200 mL of water and extracted with EtOAc (100 mL×2). The combined organic layers were washed with water (200 mL), saturated brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate=10/1 to 0/1 to give the title compound (2.00 g, 27% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 429.0 (M+H) ⁺ .

Step 3 - 1-(7-Bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione. A solution of 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (0.90 g, 2.10 mmol) in TFA (10 mL) and TfOH (0.2 mL) was stirred at 60°C for 4 hours. Upon completion, the mixture was concentrated to give a residue, which was then adjusted to pH 6-7 with TEA at 0°C. The mixture was concentrated to give a residue. The residue was suspended in EtOAc (30 mL) and stirred for 0.5 hours. The suspension was filtered and the filter cake was concentrated in vacuo to give the title compound (485 mg, 73% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.67 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.58 (s, 1H), 7.14 (d, J = 6.4 Hz, 1H), 3.80 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H). LC-MS (ESI ⁺ ) m/z 309.0(M+H) ⁺ .

2-[[5-Bromo-2-(2-methyl-4-sulfamoyl-anilino)pyrimidin-4-yl]amino]-6-fluoro-benzamide (Intermediate BA)

Step 1 - 2-((5-Bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide. To a solution of 5-bromo-2,4-dichloro-pyrimidine (5.00 g, 21.9 mmol, CAS# 36082-50-5) and 2-amino-6-fluoro-benzamide (3.72 g, 24.1 mmol, CAS# 115463-59-9) in i-PrOH (50 mL) was added DIPEA (5.67 g, 43.8 mmol) in one portion. The resulting mixture was stirred at 90 °C for 24 hours to give a yellow solution. Upon completion, the reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give the title compound (0.83 g, 72% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 10.64 (s, 1H), 8.57 (s, 1H), 8.23-8.14 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.15-7.09 (m, 1H); LC/MS (ESI, m/z): [M+1] ⁺ = 346.7.

Step 2 - 2-((5-Bromo-2-((2-methyl-4-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)-6-fluorobenzamide. To a solution of 2-((5-bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide (200 mg, 0.57 mmol) and 4-amino-3-methyl-benzenesulfonamide (108 mg, 0.57 mmol, CAS# 53297-70-4) in 2-butanol (3 mL) was added TFA (770 mg, 6.75 mmol) in one portion. The resulting mixture was stirred at 100 °C for 24 h. Upon completion, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude product was triturated with EtOH at 25 °C for 30 min to afford the title compound (55 mg, 18% yield) as a purple solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 6.30-6.27 (m, 1H), 6.29-6.27 (m, 1H), 6.22 (s, 1H), 4.46-4.44 (m, 2H), 4.19-4.17 (m, 1H), 4.14-4.12 (m, 3H), 3.9-3.96 (m, 2H), 3.93-3.92 (m, 3H), 2.26 (s, 2H); LC/MS (ESI, m/z): [M+1] ⁺ = 469.9.

4-((5-bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (Intermediate BB)

A solution of 2-[[5-bromo-2-(2-methyl-4-sulfamoyl-anilino)pyrimidin-4-yl]amino]-6-fluoro-benzamide (100 mg, 0.20 mmol) in ClSO ₃ H (0.20 mmol, 2 mL) was stirred at 80° C. for 2 h. Upon completion, the reaction mixture was poured onto ice. The mixture was then extracted with CH ₂ Cl ₂ (20 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (100 mg, 71% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 515.9 (M+H) ⁺ .

1-(Nona-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid (Intermediate BC)

Step 1 - Nona-8-yn-1-yl 4-methylbenzenesulfonate. To a mixture of nona-8-yn-1-ol (1.50 g, 10.7 mmol, CAS#10160-28-8) in DCM (20 mL) was added TosCl (2.65 g, 13.90 mmol) and TEA (3.25 g, 32.10 mmol) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The reaction mixture was partitioned between DCM (10 mL) and H ₂ O (5 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-13% ethyl acetate/petroleum ether at 60 mL/min) to afford the title compound (2.80 g, 67% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 2.8 Hz, 1H), 2.41 (s, 3H), 2.10 (dt, _J1 = 7.2 Hz, _J2 = 2.4 Hz, 2H), 1.58-1.50 (m, 2H), 1.39-1.32 (m, 2H), 1.29-1.13 (m, 6H).

Step 2 - tert-butyl 1-(nona-8-yn-1-yl)-1H-pyrazole-4-carboxylate. To a mixture of non-8-ynyl 4-methylbenzenesulfonate (2.80 g, 7.13 mmol), tert-butyl 1H-pyrazole-4-carboxylate (1.00 g, 5.95 mmol, CAS#611239-23-7) and NaOH (713 mg, 17.8 mmol) in DMF (20 mL) was added NaI (89 mg, 0.60 mmol) in one portion, then the mixture was stirred at 50 °C for 1 h. The reaction mixture was partitioned between EtOAc (10 mL) and H ₂ O (10 mL). The organic phase was separated, washed with brine (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-22% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound (1.30 g, 75% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 292.2 (M+H) ⁺ .

Step 3 - 1-(Nona-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of tert-butyl 1-non-8-ynylpyrazole-4-carboxylate (1.30 g, 4.48 mmol) in DCM (9 mL) was added TFA (4.62 g, 40.5 mmol) and the mixture was then stirred at 25°C for 12 hours. Upon completion, the reaction mixture was filtered. The crude product was purified by reverse phase flash (FA conditions) to give the title compound (950 mg, 91% yield) as a pale yellow solid. LC-MS (ESI ⁺ ) m/z 235.4 (M+H) ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ = 13.00-11.35 (m, 1H), 8.24 (s, 1H), 7.78 (s, 1H), 4.11 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 2.8 Hz, 1H), 2.13 (dt, _J1 = 6.8 Hz, _J2 = 2.8 Hz, 2H), 1.79-1.73 (m, 2H), 1.43-1.37 (m, 2H), 1.33-1.25 (m, 4H), 1.21-1.16 (m, 2H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(nona-8-yn-1-yl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BD)

To a mixture of 1-(nona-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid (137 mg, 0.58 mmol, Intermediate BC) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 0.49 mmol, Intermediate U) in MeCN (2 mL) was added _T3P (464 mg, 1.46 mmol, 50% solution in DMF) and DIPEA (94 mg, 0.73 mmol) in one portion, then the mixture was stirred at 50° C. for 48 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, elution with a gradient of 0-50% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound (150 mg, 56% yield) as a white gum. LC-MS (ESI ⁺ ) m/z 525.2 (M+H) ⁺ .

1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (Intermediate BE)

Step 1 - 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethanol (10 g, 53.1 mmol, CAS# 208827-90-1) and TosCl (12.1 g, 63.7 mmol) in DCM (110 mL) was added TEA (16.1 g, 159 mmol) and DMAP (259 mg, 2.13 mmol) in one portion. The mixture was then stirred at 0-20 °C for 12 h. Upon completion, the mixture was poured into ice water (120 mL) and extracted with DCM (2 x 120 mL). The combined organic phase was washed with brine (2 x 120 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, elution with a gradient of 0-10% ethyl acetate/petroleum ether at 80 mL/min) to give the title compound (19.8 g, 50.8 mmol, 96% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.79 (br d, J = 2.4 Hz, 2H), 7.47 (br s, 2H), 4.12 (br s, 4H), 3.62 - 3.42 (m, 10H), 2.42 (br s, 3H), 2.03 - 1.94 (m, 1H).

Step 2 - 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-methyl carboxylate and 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-methyl carboxylate. To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2 g, 5.84 mmol) and methyl 1H-pyrazole-5-carboxylate (736 mg, 5.84 mmol) in DMF (20 mL) was added KI (96.9 mg, 584 umol) and Cs ₂ CO ₃ (1.90 g, 5.84 mmol) in one portion. The resulting mixture was stirred at 20-70° C. for 12 h. Upon completion, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine (2×30 mL) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, gradient elution of 0-60% ethyl acetate/petroleum ether at 100 mL/min) to give methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (680 mg, 39% yield) as a yellow oil (LC-MS (ESI ⁺ ) m/z 297.2 (M+H) ⁺ ), and methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate (990 mg, 57% yield) as a yellow oil (LC-MS (ESI ⁺ ) m/z 297.2 (M+H) ⁺ ).

Step 3 - 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid. To a solution of methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (326 mg, 1.10 mmol) in THF (3 mL) and H ₂ O (1 mL) was added ^LiOH.H ₂ O (184 mg, 4.40 mmol) at 0° C. The mixture was then stirred at 0-20° C. for 2 hours. Upon completion, the mixture was poured into ice water (4 mL) and extracted with ethyl acetate (2×4 mL). The aqueous phase was acidified to pH=2 with aqueous HCl and extracted with ethyl acetate (2×4 mL). The combined organic phase was washed with brine (2×4 mL) and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound (280 mg) as a yellow oil. LC-MS (ESI ⁺ ) m/z 283.3 (M+H) ⁺ .

(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BF)

To a solution of 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid (280 mg, 991.88 umol, Intermediate BE) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (367 mg, 1.19 mmol, Intermediate U) in ACN (5 mL) was added _T3P (1.89 g, 2.98 mmol, 50% solution in DMF) and DIEA (641 mg, 4.96 mmol) in one portion. The resulting mixture was stirred at 20-60° C. for 12 hours. Upon completion, the mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (2×10 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a residue that was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/1) to give the title compound (530 mg, 890 umol, 90% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 573.3 (M+H) ⁺ .

1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxylic acid (Intermediate BG)

Step 1 – tert-Butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2 g, 8.68 mmol, CAS# 77279-24-4) and TEA (1.32 g, 13.0 mmol, 1.81 mL) in DCM (30 mL) was slowly added dropwise a solution of MsCl (1.19 g, 10.4 mmol) in DCM (10 mL) at 0 °C under nitrogen flow. The reaction was then stirred at 20 °C under nitrogen atmosphere for 2 h. On completion, the mixture was poured into saturated aqueous NaHCO ₃ solution (50 mL) at 0 °C and extracted with dichloromethane (40 mL × 2). The combined organic phase was washed with brine (40 mL × 2) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound (2.8 g) as a yellow oil.

Step 2 - tert-butyl 4-(2-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperazine-1-carboxylate (2.8 g, 9.08 mmol) and methyl 1H-pyrazole-5-carboxylate (1.15 _g , 9.08 mmol, CAS# 15366-34-4) in DMF (40 mL) was added KI (15 mg, 907 umol) and _Cs2CO3 (14.8 g, 45.4 mmol) at 20 °C under nitrogen flow. The reaction was then stirred at 70 °C under nitrogen atmosphere for 10 h. On completion, the reaction was poured into ice water (40 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2) and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC [column: YMC Triart C18 250 x 50 mm x 7 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 38%-68%, 22 min] to give the title compound (0.55 g, 18% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.42 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 4.64 (t, J = 6.8 Hz, 2H), 3.8 (s, 3H), 3.31 (br s, 4H), 2.72 (br t, J = 6.4 Hz, 2H), 2.39 (br s, 4H), 1.38 (s, 9H).

Step 3 - 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxylic acid. To a solution of methyl tert-butyl 4-(2-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (0.16 g, 579 umol) in THF (2 mL), MeOH (1 mL) and H ₂ O (1 mL) was added ^LiOH.H ₂ O (97.2 mg, 2.32 mmol) at 0° C. under a stream of nitrogen. The reaction was then stirred at 20° C. under a nitrogen atmosphere for 10 hours. Upon completion, the reaction was concentrated to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 1%-25%, 11.5 min) and lyophilized to give the title compound (15 mg, 98.7% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.45 (d, J = 2.0 Hz, 1H), 6.67 (d, J = .0 Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 3.23 (d, J = 2.4 Hz, 2H), 2.89 (s, 3H), 2.77 - 2.70 (m, 5H), 2.43 (br s, 3H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BH)

Step 1 - tert-butyl 4-(2-(5-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate. To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (1.15 g, 3.73 mmol, Intermediate U) and 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxylic acid (1.1 g, 3.39 mmol, Intermediate BG) in ACN (22 mL) was added _T3P (6.47 g, 10.17 mmol, 50% solution) and DIEA (2.19 g, 16.96 mmol) at 0° C. under nitrogen flow. The reaction was then stirred at 20-60° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL x 2) and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 100:1 to 0:100) to give the title compound (1.1 g, 1.79 mmol, yield 52.7%) as a colorless oil. ^1H NMR (400 MHz, CDCl3) δ = 7.54 (d, J = 2.0 Hz, 1H), 6.67 (br s, 1H), 6.20 (s, 1H), 5.13 (br s, 1H), 4.74 (t, J = 6.4 Hz, 2H), 4.68 - 4.54 (m, 1H), 3.49 - 3.27 (m, 4H), 3.16 - 3.02 (m, 1H), 2.92 - 2.79 (m, 2H), 2.54 - 2.37 (m, 5H), 1.89 - 1.73 (m, 4H), 1.66 - 1.58 (m, 8H), 1.49 - 1.39 (m, 11H), 1.19 - 1.09 (m, 6H).

Step 2 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A solution of tert-butyl 4-(2-(5-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (0.6 g, 975 umol) in HCl/dioxane (4M, 10 mL) was stirred at 20° C. for 1 h. Upon completion, the reaction was concentrated to give the title compound (502 mg, crude) as a colorless oil. LC-MS (ESI ⁺ ) m/z 645.2 (M+H) ⁺ .

Step 3 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (502 mg, 975 umol) in ACN (10 mL) was added K ₂ CO ₃ (1.35 g, 9.75 mmol) and 3-bromoprop-1-yne (116 mg, 780 umol, 80% solution) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (15 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL×2) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=100:1 to 100:70) to give the title compound (0.45 g, 814 umol, yield 83.4%) as a yellow oil. ^1H NMR (400 MHz, CDCl3) δ = 7.56 (s, 1H), 6.71 - 6.59 (m, 1H), 6.27 (s, 1H), 5.26 - 5.08 (m, 1H), 4.91 - 4.69 (m, 2H), 4.63 - 4.49 (m, 1H), 3.87 - 3.69 (m, 3H), 3.40 - 3.22 (m, 2H), 3.17 - 2.41 (m, 13H), 2.02 - 1.74 (m, 7H), 1.66 (s, 9H), 1.64 - 1.61 (m, 3H), 1.44 (s, 3H), 1.15 (dd, J = 2.0, 6.4 Hz, 8H).

1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (Intermediate BI)

Step 1 - 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-methylcarboxylate. To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.21 g, 3.55 mmol, synthesized by step 1 of intermediate BE), KI (58.9 mg, 355 umol) and _Cs2CO3 ( _3.47 g, 10.6 mmol) in DMF (13 mL) was added 1H-pyrazole-4-carboxylate (537 mg, 4.26 mmol, CAS# 181997-36-4) at 25°C, then the mixture was stirred at 70°C for 2 hours. Upon completion, the mixture was quenched with water (30 mL) and diluted with _EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL x 3) and dried over _Na2SO4 , then concentrated in vacuum. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 0/1) to give the title compound (1.10 g, yield 94%) as a colorless solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.02 (s, 1H), 7.91 (s, 1H), 4.31 (t, J = 5.2 Hz, 2H), 4.20 (d, J = 2.4 Hz, 2H), 3.86 (t, J = 5.2 Hz, 3H), 3.83 (s, 3H), 3.72 - 3.63 (m, 5H), 3.62 - 3.58 (m, 4H). LC-MS(ESI ⁺ )m/z 297.2(M+H) ⁺ .

Step 2 - 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid. A mixture of methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole- ₄ -carboxylate (1.00 g, 3.37 mmol) and ^LiOH.H2O (566 mg, 13.5 mmol) in THF (12 mL) and _H2O (4 mL) was stirred at 25°C for 12 hours. Upon completion, the mixture was quenched with sat. _NH4Cl (20 mL), diluted with EtOAc (20 mL) and extracted with water (20 mL). The layer was then acidified with HCl (1N, 4 mL) to pH<4 and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (300 mg, 28%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.11 (s, 1H), 7.97 (s, 1H), 4.35 (t, J = 5.2 Hz, 2H), 4.21 (d, J = 2.4 Hz, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.72 - 3.69 (m, 2H), 3.67 - 3.64 (m, 2H), 2.44 (t, J = 2.4 Hz, 1H), 2.12 (s, 1H). LC-MS (ESI ⁺ ) m/z 283.1(M+H) ⁺ .

(1S,3R)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BJ)

A solution of 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (200 mg, 708 umol, Intermediate BI), (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (240 mg, 779 umol, Intermediate U), DIEA (183 mg, 1.42 mmol) and _T3P (1.35 g, 2.13 mmol, 50% solution in DMF) in MeCN (8 mL) was stirred at 80° C. for 12 h. Upon completion, the mixture was quenched with sat. _NH4Cl (10 mL), diluted with EtOAc (20 mL) and extracted with EtOAc (15 mL×3). The organic layer was washed with brine (15 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=0/1) to give the title compound (70.0 mg, yield 14.6%) as a white solid. LC-MS (ESI ⁺ ) m/z 573.3 (M+H) ⁺ .

1-(3,6,9,12-Tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid (Intermediate BK)

Step 1 - 3,6,9,12-Tetraoxapentadec-14-yn-1-yl 4-methylbenzenesulfonate. To a solution of 3,6,9,12-tetraoxapentadec-14-yn-1-ol (2 g, 8.61 mmol, CAS#87450-10-0) and 4-methylbenzene-1-sulfonyl chloride (1.81 g, 9.47 mmol) in DCM (20 mL) was added TEA (2.61 g, 25.8 mmol) in one portion. The resulting mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20 °C and extracted with EtOAc mL (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (2.5 g, 75% yield) as a yellow gum: LC-MS (ESI ⁺ ) m/z 387.1 (M+H) ⁺ .

step 2 – 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-4-carboxylate. A mixture of methyl 1H-pyrazole-4-carboxylate (196 mg, 1.55 mmol, CAS #181997-36-4), 3,6,9,12-tetraoxapentadec-14-yn-1-yl ₄ -methylbenzenesulfonate (0.5 g, 1.29 mmol), _Cs2CO3 (843 mg, 2.59 mmol), KI (21.5 mg, 129 umol) in DMF (5 mL) was stirred at 70 °C under _N2 atmosphere for 1 h. On completion, the reaction mixture was quenched with _H2O (10 mL) at 20 °C and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL x 2), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 _to 1/1) to give the title compound (410 mg, 93% yield) as a yellow gum. ^1H NMR (400 MHz, DMSO-d6) δ = 8.31 (s, 1H), 7.86 (s, 1H), 4.30 (t, J = 5.2 Hz, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.73 (s, 3H), 3.56 - 3.39 (m, 13H).

Step 3 - 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid. A solution of methyl 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-4-carboxylate (400 mg, 1.18 mmol) and ^LiOH.H ₂ O (197 mg, 4.70 mmol) in THF (3 mL) and H ₂ O (1 mL) was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (10 mL×3). The aqueous phase was then adjusted to pH=3-4 and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (20 mL x 2), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure to give ^the title compound (250 mg, 65% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 12.32 (br s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 4.29 (t, J = 5.2 Hz, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.77 (t, J = 5.4 Hz, 2H), 3.55 - 3.39 (m, 13H).

(1R,3S)-3-(5-(1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BL)

To a solution of 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid (250 mg, 766 umol, Intermediate BK) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (283 mg, 919 umol, Intermediate U) in MeCN (6 mL) was added DIEA (495 mg, 3.83 mmol) and _T3P (1.46 g, 2.30 mmol, 50% solution in DMF) in one portion, then the resulting mixture was stirred at 60° C. for 6 h. Upon completion, the reaction mixture was quenched with _H2O (6 mL) at 20° C. and extracted with EtOAc (6 mL×3). The combined organic layers were washed with brine (10 mL x 2), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC ( _SiO2 , ethyl acetate:petroleum ether = 0:1) to give the title compound (153 mg, 32% yield) as a colorless gum. LC-MS (ESI ⁺ ) m/z 617.8 (M+H) ⁺ .

1-(7-Chloroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate BM)

Step 1 - 4-Bromo-7-chloroisoquinoline. To a solution of 7-chloroisoquinoline (5.00 g, 30.5 mmol, CAS#34784-06-0) in DCE (50 mL) was added PhI(OAc) ₂ (14.7 g, 45.8 mmol) and KBr (18.1 g, 152 mmol) and the mixture was stirred at 50 °C for 16 h. Upon completion, the mixture was poured into water (100 mL) and extracted with EA (300 mL). The organic layer was washed with brine (2 x 100 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in reduced pressure. The mixture was purified by silica gel column to give the title compound (5.50 g, 65% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 9.13 (s, 1H), 8.74 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 2.0, 9.2 Hz, 1H).

Step 2 - 1-(7-Chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione. To a solution of 4-bromo-7-chloroisoquinoline (2.00 g, 8.25 mmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.93 g, 8.25 mmol, intermediate CS) in DMF (20 mL) was added (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (234 mg, 1.65 mmol), CuI (314 mg, 1.65 mmol) and _K2CO3 (3.42 g, 24.7 mmol). This mixture was then stirred at 100 °C under _{N2 for} 16 h. Upon completion, the reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by reverse phase flash: (C18, 10%-40% MeCN in H ₂ O, containing 0.1% FA in H ₂ O) to give the title compound (200 mg, 5% yield) as a pale yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.31 (s, 1H), 8.60 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.83 (dd, J = 2.0, 8.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.90 - 6.86 (m, 2H), 4.83 (s, 2H), 4.00 - 3.94 (m, 1H), 3.79 - 3.76 (m, 1H), 3.73 (s, 3H), 3.19 - 3.11 (m, 1H), 2.99 - 2.92 (m, 1H).

Step 3 - 1-(7-Chloroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione. 1-(7-Chloroisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 126 umol) was added to TFA (0.5 mL) and TfOH (0.01 mL) and the mixture was stirred at 60 °C for 2 h. Upon completion, the reaction solution was diluted with water (5 mL) and then extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by prep-HPLC (column: [Phenomenex luna C18, 150 mm x 25 mm x 10 um]; mobile phase: (water (0.225% FA)-MeCN, MeCN%: 8% to 38%); 11 min) to give the title compound (5.18 mg, 14% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.56 (s, 1H), 9.31 (s, 1H), 8.59 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.84 (dd, J = 2.4, 8.8 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.75 - 3.69 (m, 1H), 3.02 - 2.94 (m, 1H), 2.78 - 2.71 (m, 1H). LC-MS(ESI ⁺ )m/z 275.9(M+H) ⁺ .

1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (Intermediate BN)

Step 1 - 8-Bromo-3-iodoimidazo[1,2-a]pyridine. To a solution of 8-bromoimidazo[1,2-a]pyridine (5.00 g, 25.3 mmol, CAS#850349-02-9) in CH ₃ CN (30 mL) (was intermediate CS), NIS (5.71 g, 25.3 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 0.5 h. Upon completion, the mixture was concentrated in vacuum. The mixture was purified by silica gel column to give the title compound (7.30 g, 89% yield) as a greenish solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.38 (d, J = 6.8 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H).

Step 2 - 1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. A mixture of 8-bromo-3-iodo-imidazo[1,2-a]pyridine (500 mg, 1.55 mmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (362 mg, 1.55 mmol, intermediate CS), CuI (58.9 mg, 309 umol), _Cs2CO3 (1.01 g, 3.10 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (44.0 _mg , 309 umol) in dioxane (10 mL) was stirred at 60 °C under _N2 for 6 h. Upon completion, the mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash (120 g flash column, Welch Ultimate XB_C18, 20-40 μm; 120 A, 5%-35% MeCN in H ₂ O, 0.5% FA in H ₂ O) and then further purified by prep-HPLC (column: Waters xbridge, 150 mm×25 mm×10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-MeCN]; B%: 22%-52%, 10 min) to give the title compound (200 mg, 10% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.35 (dd, J = 0.8, 6.8 Hz, 1H), 7.69 - 7.67 (m, 1H), 7.67 (s, 1H), 7.24 (d, J = 7.6 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.87 - 6.84 (m, 2H), 4.81 (s, 2H), 3.84 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 3.02 (s, 2H).

Step 3 - 1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. A solution of 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 116 umol) in TFA (0.5 mL) and TfOH (0.01 mL) was stirred at 70° C. for 2.5 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Waters xbridge, 150 mm x 25 mm x 10 um, water (10 mM NH ₄ HCO ₃ )-MeCN, 1% to 30% MeCN in H ₂ O, 11 min), then further purified by prep-HPLC (column: Phenomenex Luna C18, 150 mm x 25 mm x 10 um; mobile phase: [water (0.225% FA)-MeCN]; MeCN%: 0% to 20%, 11 min) to give the title compound (3.19 mg, 77% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.70 (s, 1H), 8.38 (d, J = 6.0 Hz, 1H), 7.67 - 7.65 (m, 2H), 6.91 (t, J = 6.8 Hz, 1H), 3.81 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 5.2 Hz, 2H); LC-MS (ESI ⁺ ) m/z 308.9 (M+H) ⁺ .

1-(8-chloro-4-isoquinolyl)hexahydropyrimidine-2,4-dione (intermediate BO)

Step 1 - 4-Bromo-8-chloro-isoquinoline. To a solution of 8-chloroisoquinoline (5.00 g, 30.5 mmol, CAS#34784-07-1) in AcOH (50 mL) was added NBS (7.07 g, 39.7 mmol) and the reaction mixture was then stirred at 50 °C for 40 min. Upon completion, the reaction mixture was diluted with water (100 mL) and then extracted with EA (3 x 80 mL). The combined organic layers were basified with _NaHCO3 to pH _{= 6-7 and then the mixture was extracted with EA (2 x 60 mL). The combined organic layers were dried over Na2SO4 ,} filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=100:1 to PE:EA=50:1, PE:EA=10:1, P1: R _f =0.74) to give the title compound (1.00 g, 37% yield) as a yellow solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ 9.56 (s, 1H), 8.78 (s, 1H), 8.10 - 8.03 (m, 1H), 7.73 - 7.64 (m, 2H). LC-MS(ESI ⁺ )m/z 241.9(M+H) ⁺ .

Step 2 - 1-(8-Chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione. To a solution of 4-bromo-8-chloro-isoquinoline (100 mg, 412 umol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (96.6 mg, 412.37 umol, intermediate CR) in DMF (1 mL) was added CuI (7.85 mg, 41.2 umol), (1S,2S)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (5.87 mg, 41.2 umol) and K ₃ PO ₄ (175 mg, 824 umol) then the mixture was stirred at 110° C. for 8 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was diluted with water (50 mL) and extracted with EA (5×30 mL). The combined organic layers were then dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum to give a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (15 mg, 3.06% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.89 - 9.56 (br s, 1H), 8.59 (br s, 1H), 7.73 - 7.68 (m, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.00 (s, 2H), 3.95 - 3.86 (m, 1H), 3.80 (s, 3H), 3.78 - 3.69 (m, 1H), 3.07 - 2.99 (m, 2H); LC-MS(ESI ⁺ )m/z 396.1(M+H) ⁺ .

Step 3 - 1-(8-Chloro-4-isoquinolyl)hexahydropyrimidine-2,4-dione. To a solution of 1-(8-chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (40.0 mg, 101 umol) in TFA (0.49 mL) and TfOH (0.01 mL) was then stirred at 60° C. for 2 h. Upon completion, the mixture was concentrated to give a residue and purified by prep-HPLC (0.1% FA) to give the title compound (3 mg, 10.77% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 10.59 (s, 1H), 9.56 (s, 1H), 8.71 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.85 - 7.78 (m, 1H), 4.00 - 3.93 (m, 1H), 3.75 - 3.69 (m 1H), 3.03 - 2.95 (m, 1H), 2.79 - 2.72 (m, 1H). LC-MS(ESI ⁺ )m/z 276.0(M+H) ⁺ .

3-(3-Methyl-4-(3-(3-(methylamino)propoxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate BP)

Step 1 - tert-Butyl N-methyl-N-[3-(prop-2-yn-1-yloxy)propyl]carbamate. To a stirred solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (25.00 g, 132.1 mmol) in DMF (200.0 mL) was added NaH (4.76 g, 198 mmol) portion-wise at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C under nitrogen atmosphere for 30 min. Then, propargyl bromide (23.57 g, 198.132 mmol, 1.50 equiv) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 16 h. Upon completion, the reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (500 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The resulting solution was purified by silica gel column chromatography eluting with PE/EA (30:1) to give the title compound (47.7 g, 74%) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d) δ 4.15 (d, J = 2.4 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.31 (t, J = 7.0 Hz, 2H), 2.87 (s, 3H), 2.43 (t, J = 2.4 Hz, 1H), 1.86-1.80 (m, 2H), 1.47 (s, 9H). LC/MS(ESI, m/z): [(M + 1)] ⁺ = 228.2.

Step 2 - tert-Butyl N-(3-[2-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-3H-1,3-benzodiazol-4-ylidene]ethoxy]propyl)-N-methylcarbamate. To a stirred solution of tert-butyl N-methyl-N-[3-(prop-2-yn-1-yloxy)propyl]carbamate (16.50 g, 72.59 mmol) and 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (24.5 g, 72.59 mmol, intermediate H) in DMSO (140 mL) was added Pd(PPh ₃ ) ₄ (8.39 g, 7.26 mmol) and CuI (392 mg, 7.26 mmol) and TEA (70 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours. Upon completion, the mixture was allowed to cool to room temperature. The product was purified by reverse phase flash (Column: Spherical C18, 20-40 um, 330 g; Mobile phase A: water (10 mmol/LAcOH), Mobile phase B: ACN; Flow rate: 80 mL/min; Gradient (%) B: 52%-72%, 20 min; Detector: 254/220 nm) The desired fractions were collected at 62% B) and concentrated under reduced pressure to give the title compound (9.22 g, 80% yield) as a dark yellow foam. ^1H NMR (400 MHz, chloroform-d) δ 8.20 (s, 1H), 7.19 (dd, J = 7.9, 1.0 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.78 (dd, J = 8.0, 1.1 Hz, 1H), 5.22 (dd, J = 12.5, 5.3 Hz, 1H), 4.42 (s, 2H), 3.79 (s, 3H), 3.62 (t, J = 6.3 Hz, 2H), 3.34 (t, J = 7.1 Hz, 2H), 3.03-2.92 (m, 1H), 2.89 (s, 3H), 2.87-2.68 (m, 2H), 2.33-2.20 (m, 1H), 1.92-1.81 (m, 2H), 1.47 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 485.3.

Step 3 - tert-butyl N-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]propoxy]propyl)-N-methylcarbamate. Pd/C was added to a mixture of tert-butyl N-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propyl]-N-methylcarbamate (8.00 g) in THF (200 mL) at room temperature. The reaction mixture was purged with nitrogen three times and stirred at room temperature under _H2 atmosphere for 5 hours. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (7.96 g, 88% yield) as a white solid. ^1H NMR (400 MHz, chloroform-d) δ 8.40 (s, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 5.24 (dd, J = 12.5, 5.3 Hz, 1H), 3.70 (s, 3H), 3.50-3.44 (m, 4H), 3.34-3.29 (m, 2H), 3.05-3.01 (m, 2H), 3.00-2.91 (m, 1H), 2.88 (s, 3H), 2.85-2.70 (m, 2H), 2.25-2.20 (m,1H), 1.97-1.90 (m, 2H), 1.86-1.80 (m, 2H), 1.48 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 489.3.

Step 4 - 3-(3-Methyl-4-[3-[3-(methylamino)propoxy]propyl]-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione hydrochloride. To a stirred mixture of tert-butyl N-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]propoxy]propyl)-N-methylcarbamate (8.50 g) in EA (200 mL) was added HCl (g) in 1,4-dioxane (100 mL) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by trituration with EA (100 mL) to afford the title compound (7.34 g, 96% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 8.89 (broad, 2H), 7.00-6.96 (m, 2H), 6.90-6.86 (m, 1H), 5.39 (dd, J = 12.6, 5.4 Hz, 1H), 3.57 (s, 3H), 3.49-3.43 (m, 5H), 2.98-2.86 (m, 5H), 2.77-2.57 (m, 2H), 2.52-2.48 (m, 2H), 2.05-1.95 (m, 1H), 1.94-1.80 (m, 4H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 389.3.

1-1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (intermediate BQ)

Step 1 – 2-(2-(benzyloxy)ethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-(benzyloxy)ethoxy)ethanol (10 g, 51.0 mmol, CAS# 2050-25-1) and 4-methylbenzene-1-sulfonyl chloride (11.7 g, 61.2 mmol, CAS# 98-59-9) in DCM (100 mL) was added TEA (15.5 g, 152 mmol) in one portion. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (100 mL) at 20 °C and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with a gradient of 0-100% ethyl acetate/petroleum ether at 100 mL/min) to give the title compound (15.3 g, 86% yield) as a colorless gum. ¹ H NMR (400 MHz, CD3Cl) δ 7.80 (d, J = 8.4 Hz, 2H), 7.38 - 7.27 (m, 7H), 4.54 (s, 2H), 4.31 - 4.13 (m, 2H), 3.75 - 3.66 (m, 2H), 3.64 - 3.55 (m, 4H), 2.43 (s, 3H).

step 2 - 1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate. To _a solution of 2-(2-(benzyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (5 g, 14.3 mmol) and methyl 1H-pyrazole-4-carboxylate (2.16 g, 17.1 mmol, CAS#181997-36-4) in DMF (50 mL) was added _Cs2CO3 (9.3 g, 28.5 mmol) and KI (237 mg, 1.43 mmol) in one portion. The mixture was stirred at 70 °C for 1 h. Upon completion, the reaction mixture was quenched with _H2O (50 mL) at 20 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 _to 1/1) to give the title compound (4.3 g, 99% yield) as a colorless gum. ^1H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H), 7.88 (s, 1H), 7.40 - 7.21 (m, 5H), 4.43 (s, 2H), 4.32 (t, J = 5.2 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.72 (s, 3H), 3.59 - 3.47 (m, 4H).

Step 3 - 1-1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid. To a solution of methyl 1H-pyrazole-4-carboxylate (2 g, 6.57 mmol) in THF (6 mL) and H ₂ O (3 mL) was added ^LiOH.H ₂ O (1.10 g, 26.3 mmol) in one portion and the resulting mixture was then stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (10 mL×3). The aqueous phase was then adjusted to pH=3-4 and extracted with EtOAc (10 mL×3). The organic layer was washed with brine ( ₁₀ mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give ^the title compound (1.6 g, 84% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 12.31 (br s, 1H), 8.23 (s, 1H), 7.80 (s, 1H), 7.47 - 7.13 (m, 5H), 4.44 (s, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.63 - 3.45 (m, 4H).

2-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethoxy)ethyl methanesulfonate (Intermediate BR)

Step 1 - (1R,3S)-3-(5-(1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (0.5 g, 1.72 mmol, intermediate BQ) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (531 mg, 1.72 mmol, intermediate U) in MeCN (5 mL) was added DIEA (1.11 g, 8.61 mmol) and _T3P (3.29 g, 5.17 mmol, 50% solution in DMF). The resulting mixture was stirred at 60° C. for 12 h. Upon completion, the reaction mixture was quenched with _H2O (5 mL) at 20° C. and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine ( ₁₀ mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 1/1 to 0/1) to give the title compound (560 mg, 56% yield) as a yellow gum. LC-MS (ESI ⁺ ) m/z 581.3 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(5-(1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (560 mg, 964 umol) and Pd/C (56.0 mg, 52.8 umol, 10 wt%) in THF (10 mL) was stirred at 20 °C under _H2 atmosphere (15 psi) for 1 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (393 mg, 83% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 491.3 (M+H) ⁺ .

Step 3 - 2-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethoxy)ethyl methanesulfonate. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 305 umol) and DIEA (59.2 mg, 458 umol) in DCM (3 mL) was added MsCl (220 mg, 1.96 mmol, CAS#124-63-0) dropwise at 0° C., then the mixture was stirred at 0° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (5 mL) at 0° C. and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (180 mg, 72.47% yield) as a yellow gum: LC-MS (ESI ⁺ ) m/z 569.3 (M+H) ⁺ .

3-(3-Methyl-2-oxo-4-(3-(piperidin-4-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate BS)

Step 1 - tert-Butyl 4-prop-2-ynylpiperidine-1-carboxylate. To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (500 mg, 2.20 mmol, CAS# 142374-19-4), K ₂ CO ₃ (912 mg, 6.60 mmol) in MeOH (15 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (507 mg, 2.64 mmol, CAS# 90965-06-3) at 0 °C. The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated in vacuo. The mixture was diluted with H ₂ O (30 mL) and then extracted with EA (3 x 20 mL). The organic layer was washed with brine (2×15 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the title compound (490 mg, 99% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.25 - 4.03 (m, 2H), 2.78 - 2.65 (m, 2H), 2.22 - 2.13 (m, 2H), 2.00 (t, J = 2.8 Hz, 1H), 1.85 - 1.72 (m, 2H), 1.72 - 1.60 (m, 1H), 1.48 (s, 9H), 1.30 - 1.15 (m, 2H).

Step 2 - tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]piperidine-1-carboxylate. To a solution of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (390 mg, 1.75 mmol), 3-(4-bromo-3-methyl-2-oxobenzimidazol-1-yl)piperidine-2,6-dione (393 mg, 1.16 mmol, intermediate H) in DMSO (4 mL) was added _Pd ( _PPh3 ) _2Cl2 (163 mg, 232 umol), CuI (44.3 mg, 232 umol) and DIPEA (752 mg, 5.82 mmol) under _N2 . The mixture was stirred at 80° C. for 3 hours. Upon completion, the mixture was filtered and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (450 mg, 80% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.17 - 6.95 (m, 3H), 5.45 - 5.33 (m, 1H), 4.06 - 3.89 (m, 2H), 3.63 (s, 3H), 2.98 - 2.82 (m, 1H), 2.78 - 2.69 (m, 2H), 2.66 - 2.59 (m, 1H), 2.56 - 2.52 (m, 1H), 2.49 - 2.45 (m, 2H), 2.11 - 1.97 (m, 1H), 1.82 - 1.71 (m, 3H), 1.39 (s, 9H), 1.25 - 1.10 (m, 2H), LC-MS(ESI ⁺ )m/z 503.3(M+Na) ⁺ .

Step 3 - 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. A solution of tert-butyl 4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (260 mg, 541 umol) in TFA (6 mL) and DCM (6 mL) was stirred at 25 °C for 5 h. Upon completion, the reaction mixture was quenched with H ₂ O (5 mL) and extracted with EtOAc (8 mL x 2). The pH of the aqueous phase was adjusted to 3-4 with 1N HCl, then extracted with EtOAc (8 mL×4). The combined organic layers were washed with brine (3 mL×3), dried over Na ₂ SO ₄ , and evaporated to give the title compound (220 mg) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.69 (br dd, J = 7.6, 13.2 Hz, 1H), 7.58 (dt, J = 3.6, 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.09 - 7.05 (m, 1H), 7.03 - 6.96 (m, 1H), 5.39 (dd, J = 5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 3.12 (br d, J = 12.4 Hz, 2H), 2.94 - 2.83 (m, 1H), 2.77 - 2.59 (m, 5H), 2.06 - 1.97 (m, 1H), 1.85 - 1.72 (m, 3H), 1.39 - 1.19 (m, 3H), 1.11 (s, 1H).

3-[5-(7-aminoheptyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate BT)

Step 1 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hept-6-yn-1-yl]carbamate. To a stirred mixture of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate J), tert-butyl N-(hept-6-yn-1-yl)carbamate (10.00 g, 47.32 mmol, synthesized by steps 1-4 of intermediate AN) and CuI (0.45 g, 2.37 mmol) in DMSO (40.00 mL)/TEA (20.00 mL) was added Pd(PPh ₃ ) ₄ (2.73 g, 2.37 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 85° C. for 4 hours. Upon completion, the mixture was allowed to cool to room temperature. The reaction was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:2), then further purified by reverse-phase flash chromatography (column: WelFlash™ C18-I, 20-40 μm, 330 g; eluent A: water (plus 10 mmol/L FA); eluent B: ACN; gradient: 40% to 65% B in 20 min; flow rate: 80 mL/min; detector: 220/254 nm; desired fractions were collected at 60% B) and concentrated under reduced pressure to give the title compound (7.5 g, 68% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.13 (s, 1H), 7.25-7.23 (m, 1H), 7.11-7.07 (m, 2H), 6.82 (t, J = 5.8 Hz, 1H), 5.38 (dd, J = 12.7, 5.3 Hz, 1H), 3.35 (s, 3H), 2.95-2.81 (m, 3H), 2.79-2.56 (m, 2H), 2.41 (t, J = 7.0 Hz, 2H), 2.05-1.99 (m, 1H), 1.54 (t, J = 7.0 Hz, 2H), 1.41-1.37 (m, 13H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 469.3.

Step 2 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]heptyl]carbamate. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hept-6-yn-1-yl]carbamate (8.00 g, 17.0 mmol) in MeOH (200.00 mL)/AcOH (10.00 mL) was added Pd/C (1.00 g, 9.40 mmol) at room temperature under nitrogen atmosphere. The reaction was purged with H ₃ times and stirred at t for 16 h under hydrogen atmosphere. Upon completion, the reaction mixture was filtered and the filter cake was washed with CH ₂ Cl ₂ (3×20 mL). The filtrate was concentrated under reduced pressure to give the title compound (7.5 g, 93% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.05-6.96 (m, 2H), 6.88-6.84 (m,1H), 6.76 (t, J = 5.8 Hz, 1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 3.35 (s, 3H), 2.91-2.86 (m, 3H), 2.78-2.55 (m, 4H), 2.03-1.98 (m, 1H), 1.58 (t, J = 7.4 Hz, 2H), 1.37 (s, 9H), 1.32-1.17 (m, 6H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 473.3.

Step 3 - 3-[5-(7-aminoheptyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]heptyl]carbamate (7.50 g, 15.9 mmol) in DCM (20.0 mL) was added HCl (4 M) in 1,4-dioxane (20.0 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours. Upon completion, the mixture was concentrated under reduced pressure. The residue was triturated with Et ₂ O to give the title compound (6.3 g, 97% yield) as an off-white solid. ^1H NMR (300 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.92 (broad, 3H), 7.07-6.96 (m, 2H), 6.88-6.84 (m, 1H), 5.35 (dd, J = 12.8, 5.3 Hz, 1H), 3.32 (s, 3H) 3.02-2.82 (m, 1H), 2.78-2.71 (m, 3H), 2.68-2.56 (m, 3H), 2.06-1.95 (m, 1H), 1.62-1.51 (m, 4H), 1.32-1.27 (m, 6H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 373.3.

1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate BU)

Step 1 - 1-(4-formylphenyl)-1H-pyrazole-4-methyl carboxylate. To a solution of (4-formylphenyl)boronic acid (10 g, 66.7 mmol, CAS# 87199-17-5) and 1H-pyrazole-4-methyl carboxylate (12.6 g, 100 mmol, CAS# 51105-90-9) in pyridine (100 mL) was added Cu(OAc) ₂ (24.2 g, 133 mmol). The mixture was stirred at 20-100° C. for 12 hours. Upon completion, the mixture was poured into ice water (100 mL) and filtered, then the mixture was extracted with ethyl acetate (2×100 mL). The combined organic phase was washed with brine (2×100 mL) and dried over sodium sulfate. Then filtered to obtain the filtrate and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with a gradient of 0-50% ethyl acetate/petroleum ether at 100 mL/min) to give the title compound (1.5 g, 6.52 mmol, 10% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.59 (br s, 1H), 10.04 (s, 1H), 9.79 (s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H).

Step 2 - Methyl 1-[4-(1,3-dioxolan-2-yl)phenyl]pyrazole-4-carboxylate. To a solution of methyl 1-(4-formylphenyl)-1H-pyrazole-4-carboxylate (1 g, 4.34 mmol) in toluene (10 mL) was added ethylene glycol (808 mg, 13.0 mmol) and 4-methylbenzenesulfonic acid (74.8 mg, 434 umol). The mixture was stirred at 20-130° C. for 4 hours. Upon completion, the mixture was poured into ice water (13 mL) and extracted with ethyl acetate (2×13 mL). The combined organic phase was washed with brine (2×13 mL) and then dried over sodium sulfate. It was then filtered to obtain the filtrate and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a gradient of 0-18% ethyl acetate/petroleum ether at 40 mL/min) to give the title compound (500 mg, 929 umol, 21% yield) as a yellow oil. LC-MS (ESI+) m/z 231.0 (M+H) ⁺ .

Step 3 - 1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylic acid. To a solution of methyl 1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (400 mg, 1.46 mmol) in THF (3 mL), H ₂ O (1 mL) and MeOH (1 mL) was added LiOH. H ₂ O (244 mg, 5.83 mmol) in one portion. The mixture was stirred at 20°C for 10 h. Upon completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The aqueous phase was acidified to pH = 4 with aqueous HCl (1 N) and extracted with ethyl acetate (2 x 5 mL). The combined organic phase was washed with brine (2 x 5 mL) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give the title compound (300 mg) as a white solid: LC-MS (ESI+) m/z 261.1 (M+H) ⁺ .

(1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BV) and (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate BW)

Step 1 - (1R,3S)-3-(5-(1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylic acid (300 mg, 1.15 mmol, intermediate BU) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (355 mg, 1.15 mmol, intermediate U) in ACN (3 mL) was added _T3P (2.20 g, 3.46 mmol, 50% solution in DMF) and DIEA (745 mg, 5.76 mmol) in one portion. The mixture was stirred at 20-60° C. for 12 hours. Upon completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic phase was washed with brine (2×5 mL) and dried over sodium sulfate. The reaction was then filtered and the filtrate was concentrated to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, gradient elution of 0-50% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound (420 mg, 541 umol, 47% yield) as a yellow oil. LC-MS (ESI+) m/z 551.3 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate and (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-(5-(1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (400 mg, 726 umol) was added HCl (2M, 2 mL) in THF (2.4 mL). The mixture was stirred at 60° C. for 24 h. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 39%-69%, 10 min) to give (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (100 mg, 197 umol, 27% yield) as a yellow oil ( ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.04 (s, 1H), 9.79 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 9.89 (s, 1H), 9.77 (s, 1H), 9.9 ... 8.18 - 8.12 (m, 2H), 8.11 - 8.06 (m, 2H), 6.02 (s, 1H), 5.75 (s, 1H), 5.10 - 4.92 (m, 1H), 3.62 - 3.52 (m, 1H), 3.05 - 2.96 (m, 1H), 2.00 - 1.82 (m, 3H), 1.75 - 1.66 (m, 3H), 1.53 (s, 9H), 1.02 (d, J = 6.4 Hz, 6H)) and (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 111 umol, 15% yield) as a yellow oil ( ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.31 - 12.06 (m, 1H), 10.60 (s, 1H), 10.04 (s, 1H), 9.27 (s, 1H), 8.41 (s, 1H), 8.22 - 7.90 (m, 4H), 7.06 - 6.85 (m, 1H), 6.43 (br s, 1H), 5.01 (br d, J = 4.4 Hz, 1H), 3.58 (qd, J = 6.8, 13.6 Hz, 1H), 3.14 - 2.99 (m, 1H), 2.10 - 1.38 (m, 6H), 1.03 (d, J = 6.4 Hz, 6H)).

tert-Butyl methyl (prop-2-yn-1-yl)carbamate (Intermediate BX)

To a solution of tert-butyl N-methylcarbamate (10.0 g, 76.2 mmol, CAS#16066-84-5) in DMF (100 mL) was added NaH (3.66 g, 91.5 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. Then 3-bromoprop-1-yne (13.6 g, 114 mmol, CAS#106-96-7) was added. The mixture was stirred at 25 °C for 2.5 h. Upon completion, the reaction mixture was quenched by addition of H ₂ O (50 mL) and extracted with dichloromethane (3 x 500 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to give the title compound (4.80 g, 37% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d6) δ 3.98 (d, J = 2.0 Hz, 2H), 3.19 (s, 1H), 2.80 (s, 3H), 1.40 (s, 9H).

3-(3-methyl-4-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (intermediate BY)

Step 1 - tert-Butyl (3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)(methyl)carbamate. To a solution of N-methyl-N-prop-2-ynyl-tert-butylcarbamate (2.00 g, 11.8 mmol, Intermediate BX), 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.66 g, 7.88 mmol, Intermediate H), CuI (150 mg, 787 umol), Pd(PPh ₃ ) ₂ Cl ₂ (553 mg, 787 umol), 4A molecular sieves (1.00 g, 7.88 mmol) and Cs ₂ CO ₃ (10.2 g, 31.5 mmol) in DMF (50 mL). The mixture was stirred at 80 °C under N ₂ for 16 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash (0.1% FA) to give the title compound (600 mg, 16% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.23 - 6.90 (m, 3H), 5.44 - 5.35 (m, 1H), 4.29 (s, 2H), 3.61 (s, 3H), 3.54 (s, 1H), 2.89 (s, 2H), 2.95 - 2.80 (m, 1H), 2.77 - 2.59 (m, 2H), 2.07 - 1.96 (m, 1H), 1.42 (s, 9H).

Step 2 - 3-(3-methyl-4-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. To a solution of tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-N-methyl-carbamate (100 mg, 234 umol) in DCM (10 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25°C for 20 minutes. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (750 mg, 95% yield, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 349.2 (M+23) ⁺ .

1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (Intermediate BZ)

To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate H) in DMF (20 mL) was added TEA (448 mg, 4.44 mmol), Pd(dppf)Cl ₂ (162 mg, 221 umol) and Et ₃ SiH (515 mg, 4.44 mmol). The reaction mixture was stirred at 80° C. under CO (50 Psi) for 16 h. Upon completion, the reaction mixture was concentrated in vacuo and purified by reverse phase (0.1% FA) to give the title compound (400 mg, 47% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 288.0 (M+H) ⁺ .

3-[4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate CA)

Step 1 - tert-butyl 9-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate. To a solution of 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (100 mg, 348 umol, Intermediate BZ) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (88.5 mg, 348 umol, CAS# 173405-78-2) in THF (3 mL) and DMF (3 mL) was added tetraisopropoxytitanium (296 mg, 1.04 mmol, 308 uL). The mixture was stirred at 80° C. for 2 hours, then NaBH(OAc) ₃ (147 mg, 696 umol) was added to the mixture. The reaction mixture was stirred at 20° C. for 16 hours. Upon completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (145 mg, 79% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.90 - 6.85 (m, 1H), 5.37 (dd, J = 5.2, 12.4 Hz, 1H), 3.66 (s, 3H), 3.65 - 3.60 (m, 2H), 3.30 - 3.23 (m, 4H), 2.94 - 2.84 (m, 1H), 2.77 - 2.68 (m, 1H), 2.65 - 2.57 (m, 1H), 2.43 - 2.34 (m, 4H), 2.05 - 1.96 (m, 1H), 1.45 - 1.39 (m, 4H), 1.38 (s, 9H), 1.36 - 1.30 (m, 4H); LC-MS(ESI ⁺ )m/z 526.2(M+H) ⁺ .

Step 2 - 3-[4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione. To a solution of tert-butyl 9-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (70.0 mg, 133 umol) in DCM (1.5 mL) was added HCl/EtOAc (4M, 1.50 mL). The reaction mixture was stirred at 20° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (60.0 mg, 97% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 426.3 (M+H) ⁺ .

(1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate CB)

Step 1 - Benzyl (1-(tert-butyl)-3-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (10.0 g, 27.9 mmol, Intermediate AH) and 4-nitrophenyl carbonochloridate (8.46 g, 41.9 mmol, CAS# 7693-46-1) in dichloromethane (100 mL) was added DMAP (342 mg, 2.80 mmol) and pyridine (6.64 g, 83.9 mmol). The mixture was stirred at 20° C. for 12 hours. Upon completion, the reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (eluted with petroleum ether/ethyl acetate = 3:1 to 1/1) to give the title compound (14 g, 26.7 mmol, 96% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.22 - 8.16 (m, 2H), 7.34 - 7.24 (m, 6H), 6.19 - 6.02 (m, 2H), 5.23 - 5.12 (m, 3H), 3.13 - 3.00 (m, 1H), 2.59 - 2.48 (m, 1H), 2.08 - 1.78 (m, 6H), 1.51 (s, 9H).

Step 2 - (1-(tert-butyl)-3-((1R,3S)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate. To a mixture of (1-(tert-butyl)-3-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (14 g, 26.7 mmol) and propan-2-amine (3.17 g, 53.5 mmol) in THF (140 mL) was added DIEA (17.3 g, 133 mmol) in one portion at 0 °C under _N2 . This mixture was stirred at 20 °C for 10 h. Upon completion, the reaction mixture was quenched with water (100 mL) and then extracted with dichloromethane (3 x 140 mL). The combined organic layers were washed with brine (3×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (eluted with petroleum ether/ethyl acetate=3:1 to 1/1) to give the title compound (10.8 g, 24.5 mmol, 92% yield) as a colorless gum. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.52 - 7.46 (m, 1H), 7.38 (br s, 4H), 6.32 (br s, 1H), 6.13 (br s, 1H), 5.30 (s, 1H), 5.22 - 5.18 (m, 2H), 5.09 - 5.07 (m, 1H), 3.80 (br d, J = 5.6 Hz, 1H), 3.10 (br d, J = 7.6 Hz, 1H), 2.52 - 2.37 (m, 1H), 2.04 - 1.98 (m, 1H), 1.97 - 1.72 (m, 5H), 1.58 (s, 8H), 1.14 (br d, J = 6.4 Hz, 6H).

Step 3 - (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of Pd/C (3.24 g, 3.06 mmol, 10 wt %) in ethanol (300 mL) was added (1-(tert-butyl)-3-((1R,3S)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzylcarbamate (10.8 g, 24.4 mmol) under a stream of nitrogen. The suspension was degassed under reduced pressure and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 20° C. for 10 hours. Upon completion, the reaction was filtered to obtain the filtrate and concentrated to give the title compound (5.1 g) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 5.2 (br s, 1H), 4.44 (br s, 1H), 3.8 (br d, J = 4.4 Hz, 1H), 3.53 (br s, 2H), 3.11 - 2.94 (m, 1H), 2.55 - 2.41 (m, 1H), 2.05 - 1.72 (m, 6H), 1.62 (s, 9H), 1.15 (d, J = 6.4 Hz, 6H).

2-(2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid (Intermediate CC)

Step 1 - Methyl 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetate. To a solution of methyl 2-(2-hydroxyphenyl)acetate (993 mg, 5.98 mmol, CAS# 22446-37-3), 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethanol (1.35 g, 7.17 mmol, CAS# 208827-90-1) and _PPh3 (2.04 g, 7.77 mmol) in toluene (10 mL) was slowly added dropwise a solution of DIAD (1.57 g, 7.77 mmol, 1.51 mL) in toluene (10 mL) at 0 °C. The reaction was then stirred at 20 °C under nitrogen atmosphere for 10 h. Upon completion, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 1/1) to give the title compound (625 mg, 1.86 mmol, 31% yield) as a colorless gum. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.27 - 7.22 (m, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.21 (d, J = 2.4 Hz, 2H), 4.14 (t, J = 5.2 Hz, 2H), 3.84 (t, J = 5.2 Hz, 2H), 3.76 - 3.63 (m, 14H), 2.43 (t, J = 2.4 Hz, 1H).

Step 2 - 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid. To a solution of methyl 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetate (625 mg, 1.86 mmol) in THF (6 mL) and H ₂ O (2 mL) was added ^LiOH.H ₂ O (311 mg, 7.43 mmol) in one portion. The mixture was stirred at 20° C. for 10 h. Upon completion, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×20 mL) and the aqueous phase was acidified to pH=4 with 1N HCl. The mixture was then extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (220 mg) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.26 - 7.22 (m, 1H), 7.21 - 7.18 (m, 1H), 6.95 - 6.91 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.21 (d, J = 2.4 Hz, 2H), 4.19 - 4.17 (m, 2H), 3.82 (td, J = 2.0, 4.4 Hz, 2H), 3.79 - 3.69 (m, 10H), 3.61 (s, 2H), 2.43 (t, J = 2.4 Hz, 1H), 1.29 - 1.24 (m, 1H).

Isopropylcarbamate 1S,3R)-3-(1-(tert-butyl)-5-(2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetamido)-1H-pyrazol-3-yl)cyclopentyl (Intermediate CD)

To a solution of (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (210 mg, 682 umol, Intermediate CB) in ACN (5 mL) was added 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid (220 mg, 682 umol, Intermediate CC), DIEA (441 mg, 3.41 mmol) and _T3P (1.30 g, 2.05 mmol, 50% solution in DMF) in one portion. The mixture was then stirred at 60° C. under nitrogen atmosphere for 2 hours. Upon completion, the reaction mixture was poured into saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, elution with a gradient of 0-50% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound (95 mg, 154 umol, 23% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.26 - 7.20 (m, 2H), 6.93 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 5.06 (br s, 1H), 4.67 - 4.49 (m, 1H), 4.13 - 4.10 (m, 4H), 3.82 - 3.79 (m, 2H), 3.69 (s, 2H), 3.58 (br dd, J = 3.6, 5.6 Hz, 4H), 3.53 (dd, J = 4.0, 5.6 Hz, 2H), 3.47 (dd, J = 3.6, 5.6 Hz, 2H), 3.38 - 3.31 (m, 2H), 3.07 - 2.93 (m, 1H), 2.35 (t, J = 2.4 Hz, 2H), 1.92 - 1.66 (m, 6H), 1.23 (s, 9H), 1.07 (dd, J = 3.2, 6.4 Hz, 6H).

3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-methylpiperidine-2,6-dione (Intermediate CE)

To a solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol, intermediate J) in DMF (16 mL) was added NaH (141 mg, 3.55 mmol, 60% dispersion in mineral oil) in portions. The mixture was stirred at 0 °C under _N2 atmosphere for 30 min. Then MeI (503 mg, 3.55 mmol) was added to the mixture, which was then stirred at 25 °C for 12 h. The reaction mixture was quenched with _NH4Cl (sat. aq, 20 mL) at 25 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine ( ₂₀ mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 0/1) to give the title compound (850 mg, 2.41 mmol, 82% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 354.2 (M+H) ⁺ .

3-(3-Methyl-2-oxo-5-(3-(4-(piperazin-1-yl)butoxy)propyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate CF)

Step 1 - tert-butyl 4-(4-hydroxybutyl)piperazine-1-carboxylate. To a stirred solution of tert-butyl piperazine-1-carboxylate (39.00 g, 209.4 _mmol ) and 4-bromobutan-1-ol (48.06 g, 314.1 mmol) in ACN (1000 mL) was added _K2CO3 (115.76 g, 837.6 mmol) and KI (17.38 g, 104.7 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. Upon completion, the mixture was allowed to cool to room temperature and filtered. The filter cake was washed with MeCN (3 x 50 mL) and the filtrate was concentrated under reduced pressure. The residue was quenched with water and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with _CH2Cl2 /MeOH (30:1) to give the title compound ( _19.7 g, 36% yield) as a pale yellow oil. ^1H NMR (400 MHz, chloroform-d) δ 5.62-5.57 (m, 1H), 3.57 (t, J = 4.9 Hz, 2H), 3.49-3.41 (m, 4H), 2.46-2.42 (m, 4H), 2.42-2.37 (m, 2H), 1.69-1.63 (m, 4H), 1.45 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 259.3.

Step 2 - tert-butyl 4-[4-(prop-2-yn-1-yloxy)butyl]piperazine-1-carboxylate. To a stirred solution of tert-butyl 4-(4-hydroxybutyl)piperazine-1-carboxylate (31.50 g, 121.9 mmol) in DMF (300.00 mL) was added NaH (5.85 g, 244 mmol, 60% dispersion in mineral oil) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 30 minutes. To the above mixture was added a solution of propargyl bromide (29.01 g, 243.9 mmol) in DMF (50.00 mL) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. Upon completion, the reaction was subjected to sat. The mixture was quenched with NH ₄ Cl (aq.) at 0° C. and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc=5/1 to give the title compound (19.7 g, 55% yield) as a brown oil. ^1H NMR (400 MHz, chloroform-d) δ 4.14 (d, J = 2.4 Hz, 2H), 3.54 (t, J = 6.1 Hz, 2H), 3.48-3.41 (m, 4H), 2.43 (t, J = 2.4 Hz, 1H), 2.42-2.34 (m, 6H), 1.71-1.53 (m, 4H), 1.47 (s, 9H). LC/MS (ESI, m/z): [(M + 1)] ⁺ = 297.3.

Step 3 - tert-butyl 4-[4-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)butyl]piperazine-1-carboxylate. To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (10.00 g, 29.572 mmol, intermediate J) and tert-butyl 4-[4-(prop-2-yn-1-yloxy)butyl]piperazine-1-carboxylate (13.15 g, 44.36 mmol) in DMSO (200.00 mL) and TEA (49.20 mL) was added Pd(PPh ₃ ) ₄ (3.42 g, 2.96 mmol) and CuI (0.56 g, 2.9 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was purged with nitrogen three times. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours. Upon completion, the mixture was allowed to cool to room temperature and diluted with water (100 mL). The resulting mixture was washed with EA (3×150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (20:1) to give the title compound (8.3 g, yield 51%) as a yellow oil. ^1H NMR (400 MHz, chloroform-d) δ 8.81 (s, 1H), 7.20 (dd, J = 8.1, 1.5 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 5.21 (dd, J = 12.7, 5.3 Hz, 1H), 4.36 (s, 2H), 3.60 (t, J = 6.1 Hz, 2H), 3.46-3.42 (m, 7H), 3.01-2.88 (m, 1H), 2.88-2.66 (m, 2H), 2.42-2.36 (m, 6H), 2.28-2.17 (m, 1H), 1.70-1.59 (m, 4H), 1.47 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 554.4.

Step 4 - tert-Butyl 4-(4-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]butyl)piperazine-1-carboxylate. To a stirred solution of tert _- butyl 4-[4-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)butyl]piperazine-1-carboxylate (8.00 g, 14.4 mmol) in CH OH (100.00 mL) and THF (10.00 mL) was added Pd/C (4.00 g, 37.6 mmol) at room temperature. The resulting mixture was purged with hydrogen three times and stirred at room temperature under hydrogen atmosphere overnight. Upon completion, the mixture was filtered and the filter cake was washed with THF (3×30 mL). The solution was concentrated under reduced pressure to give the title compound (7.5 g) as a pale yellow oil. LC/MS (ESI, m/z): [(M + 1)] ⁺ = 558.4.

Step 5 - 3-(3-Methyl-2-oxo-5-[3-[4-(piperazin-1-yl)butoxy]propyl]-1,3-benzodiazol-1-yl)piperidine-2,6-dione dihydrochloride. To a stirred solution of tert-butyl 4-(4-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]butyl)piperazine-1-carboxylate (7.50 g, 13.5 mmol) in DCM (100.00 mL) was added 4M HCl (gas) in 1,4-dioxane (30.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. Upon completion, Et ₂ O (200 mL) was added to this mixture. The precipitated solid was collected by filtration and washed with Et ₂ O (3×100 mL) to give the title compound (5 g, 70% yield) as a pale yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.56 (broad, 1H), 11.08 (s, 1H), 9.52 (broad, 2H), 7.05 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.88 (dd, J = 8.1, 1.6 Hz, 1H), 5.35 (dd, J = 12.7, 5.4 Hz, 1H), 3.68-3.64 (m, 2H), 3.51-3.36 (m, 9H), 3.27-3.11 (m, 4H), 2.99-2.86 (m, 1H), 2.78-2.58 (m, 4H), 2.56-2.53 (m, 2H), 2.03-1.97 (m, 1H), 1.93-1.66 (m, 4H), 1.58-1.53 (m, 2H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 458.3.

3-(4-(3-(3-(3-aminopropoxy)propoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate CG)

Step 1 - tert-Butyl N-[3-(methanesulfonyloxy)propyl]carbamate. To a stirred solution of tert-butyl N-(3-hydroxypropyl)carbamate (92.6 g, 528 mmol) and TEA (109.8 mL, 792.7 mmol) in DCM (800 mL) was added a solution of Ms-Cl (60.5 g, 528 mmol) in DCM (200 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 min. Upon completion, the reaction mixture was diluted with water (2 L) and extracted with CH ₂ Cl ₂ (3 x 800 mL). The combined organic layers were washed with brine (1.5 L) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:2) to give the title compound (112 g, 84% yield) as a light brown solid. ¹ H NMR (400 MHz, chloroform-d) δ 4.93-4.90 (m, 1H), 4.26-4.22 (m, 2H), 3.24-3.19 (m, 2H), 3.01 (s, 3H), 1.94-1.88 (m, 2H), 1.38 (s, 9H). LC/MS(ESI, m/z): [(M + 1)] ⁺ = 254.2.

Step 2 - tert-Butyl N-[3-(3-hydroxypropoxy)propyl]carbamate. To a solution of propane-1,3-diol (50 g, 657 mmol) in DMF (500 mL) was added sodium hydride (4.8 g, 200 mmol, 60% dispersion in mineral oil) at 0°C. The mixture was stirred for 15 min. To the above mixture was added a solution of tert-butyl N-[3-(methanesulfonyloxy)propyl]carbamate (25.3 g, 100 mmol) in DMF (150 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Upon completion, the reaction was quenched with sat. NH ₄ Cl(aq.) (200 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with brine (1.5 L) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give the title compound (13.7 g, 59% yield) as a pale yellow oil. ^1H NMR (400 MHz, chloroform-d) δ 5.05-5.02 (m, 1H), 3.69-3.64 (m, 2H), 3.52-3.49 (m, 2H), 3.43-3.40 (m, 2H), 3.15-3.109 (m, 3H), 1.77-1.72 (m, 2H), 1.69-1.64 (m,2H), 1.37 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 234.2.

Step 3 - tert-Butyl N-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate. To a solution of tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate (12.5 g, 53.6 mmol) in THF (300 mL) was added sodium hydride (2.6 g, 110 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred for 15 min. Then, a solution of 3-bromoprop-1-yne (6.4 g, 54 mmol) in THF (50 mL) was added and the mixture was allowed to warm to room temperature and stirred for 16 h. Upon completion, the reaction was quenched with sat. NH4Cl(aq.) (200 mL) at 0 °C. The resulting mixture was diluted with brine (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (500 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:1) to give the title compound (9.2 g, 60% yield) as a light yellow solid. ^1H NMR (400 MHz, chloroform-d) δ 4.93 (broad, 1H), 4.11 (d, J = 2.4 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.46 (q, J = 6.2 Hz, 4H), 3.19 (d, J = 7.6 Hz, 2H), 2.42 (t, J = 2.4 Hz, 1H), 1.83 (p, J = 6.3 Hz, 2H), 1.71 (p, J = 6.2 Hz, 2H), 1.41 (s, 9H). LC/MS(ESI, m/z): [(M + 1)] ⁺ = 272.3.

Step 4 - tert-butyl N-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate. To a stirred solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione (2 g, 5.9 mmol, intermediate H), tert-butyl N-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (3 g, 11 mmol) and TEA (15 mL) in DMA (30 mL) was added CuI (112.64 mg, 0.591 mmol) and Pd(PPh ₃ ) ₄ (683.44 mg, 0.591 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 6 hours. Upon completion, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, ACN (10 mmol/L) in aq. FA, gradient 35% to 60% over 15 min; detector, UV 254 nm) to give the title compound (1.4 g, 45% yield) as a light brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.18 (dd, J = 7.9, 1.2 Hz, 1H), 7.13 (dd, J = 7.9, 1.2 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.76-6.72 (m, 1H), 5.41 (dd, J = 12.7, 5.4 Hz, 1H), 4.43 (s, 2H), 3.64 (s, 3H), 3.62-3.55 (m, 2H), 3.42 (t, J = 6.4 Hz, 2H), 3.35 (d, J = 12.6 Hz, 2H), 3.01-2.82 (m, 3H), 2.77-2.56 (m, 2H), 2.06-1.99 (m, 1H), 1.82-1.74 (m, 2H), 1.62-1.55 (m, 2H), 1.37 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 529.3.

Step 5 - tert-Butyl N-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate. To a stirred solution of tert-butyl N-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate (600 mg, 1 mmol) in THF (15 mL) was added Pd/C (300 mg, 0.3 mmol, 10 wt %) at room temperature under nitrogen atmosphere. The resulting mixture was purged with _H2 three times and stirred at room temperature under hydrogen atmosphere for 4 h. Upon completion, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (580 mg, 96% yield) as a light brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.00-6.94 (m, 2H), 6.88-6.84 (m, 1H), 6.79-6.76 (m, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 3.57 (s, 3H), 3.48-3.39 (m, 6H), 3.37-3.34 (m, 2H), 3.01-2.84 (m, 5H), 2.79-2.57 (m, 2H), 2.06-1.95 (m, 1H), 1.86-1.80 (m, 2H), 1.79-1.69 (m, 2H), 1.64-1.57 (m, 2H), 1.37 (s, 9H). LC/MS(ESI, m/z): [(M+1)] ⁺ = 533.3.

Step 6 - 3-(4-[3-[3-(3-aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate (580 mg, 1.1 mmol) in 1,4-dioxane (7 mL) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. Upon completion, the mixture was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (10 mL) and concentrated again under reduced pressure to give the title compound (489 mg, crude yield 96%) as a light green solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.11 (s, 1H), 7.81 (broad, 3H), 7.05-6.95 (m, 2H), 6.89-6.85 (m, 1H), 5.38 (dd, J = 12.5, 5.4 Hz, 1H), 3.58 (s, 3H), 3.45-3.41 (m, 8H), 3.01-2.78 (m, 5H), 2.78-2.58 (m, 2H), 2.06-1.95 (m, 1H), 1.90-1.69 (m, 6H). LC/MS (ESI, m/z): [(M + 1)] ⁺ = 433.3.

4-[(7'-cyclopentyl-6'-oxo-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino]-3-methyl-benzenesulfonyl chloride (intermediate CH)

Step 1 - Ethyl 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)cyclopropanecarboxylate. To a solution of NaH (2.43 g, 60.8 mmol, 60% dispersion in mineral oil) in DMF (60 mL) at 0°C was slowly added then a solution of 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)ethyl acetate (6 g, 24.3 mmol, CAS#61727-34-2) and 1,2-dibromoethane (6.85 g, 36.5 mmol, CAS#106-93-4) in DMF (60 mL) at 0°C. The solution was then stirred at 25°C for 0.5 h. On completion, the mixture was slowly poured into sat. NH ₄ Cl (60 mL) at 0°C and the solution was extracted with EtOAc (50 ml×3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 10/1) to give the title compound (4.5 g, 63% yield) as a yellow oil: LC-MS (ESI ⁺ ) m/z 272.9 (M+H) ⁺ .

Step 2 - Ethyl 1-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)cyclopropanecarboxylate. To a solution of ethyl 1-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)cyclopropanecarboxylate (4.8 g, 17.6 mmol) in dioxane (10 mL) was added TEA (2.67 g, 26.4 mmol) and cyclopentanamine (3.75 g, 44.0 mmol). The mixture was then stirred at 60° C. for 12 h. Upon completion, the mixture was diluted with water (20 ml) and extracted with CH ₂ Cl ₂ (20 ml×3). The organic layer was washed with brine (20 ml×3) and then the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=8/1 to 4/1) to give the title compound (5 g, 85% yield) as a red oil. LC-MS (ESI ⁺ ) m/z 322.0 (M+H) ⁺ .

Step 3 - 7'-Cyclopentyl-2'-(methylthio)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. To a solution of ethyl 1-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]cyclopropanecarboxylate (4.8 g, 14.9 mmol) in THF (80 mL) was added NaH (1.19 g, 29.9 mmol, 60% dispersion in mineral oil). The mixture was then stirred at 0-60°C for 1 h. Upon completion, the mixture was quenched with HCl (1M, 20 ml) at 0°C and then the solution was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml x 3) and the organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 10/1) to give the title compound (3.2 g, 73% yield) as a yellow oil: LC-MS (ESI ⁺ ) m/z 276.0 (M+H) ⁺ .

Step 4 - 7'-Cyclopentyl-2'-(methylsulfonyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. To a solution of 7'-cyclopentyl-2'-methylsulfanyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (1 g, 3.63 mmol) in THF (15 mL) and H ₂ O (15 mL) was added Oxone (5.58 g, 9.08 mmol). The mixture was then stirred at 30°C for 4 hours. Upon completion, the reaction mixture was filtered to obtain a solution. The solution was then diluted with water (20 ml) and extracted with EtOAc (20 ml x 3). The combined organic layer was washed with brine (20 ml x 3) and the organic layer was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 2/1) to give the title compound (1.1 g, 98% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 308.0 (M+H) ⁺ .

Step 5 - 2'-((4-(benzylthio)-2-methylphenyl)amino)-7'-cyclopentylspiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. To a solution of 7'-cyclopentyl-2'-methylsulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (0.3 g, 976 umol) in toluene (10 mL) was added Pd(OAc) ₂ (21.9 mg, 97.6 umol) and BINAP (91.2 mg, 146 umol), _Cs2CO3 ( ₉₅₄ mg, 2.93 mmol), 4A molecular sieves (300 mg, 976 umol) and 4-benzylsulfanyl-2-methyl-aniline (224 mg, 976 umol, intermediate M). The mixture was stirred at 100 °C under _N2 atmosphere for 12 h. On completion, the reaction mixture was poured into water (30 ml) and extracted with EtOAc (10 ml × 3). The organic layer was dried over Na ₂ SO ₄ and the solution was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=8/1-3/1) and pre-HPLC (FA conditions) to give the title compound (74 mg, 13% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 457.0 (M+H) ⁺ .

Step 6 - 4-((7'-Cyclopentyl-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-3-methylbenzene-1-sulfonyl chloride. To a solution of 2'-(4-benzylsulfanyl-2-methyl-anilino)-7'-cyclopentyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (50 mg, 110 umol) in AcOH (1 mL) and HCl (0.3 mL) was added NCS (58.5 mg, 438 umol) at 0°C. The mixture was then stirred at 0-25°C for 10 minutes. On completion, the mixture was diluted with water (5 ml) and extracted with EtOAc (5 ml x 3). The organic layer was dried over Na ₂ SO ₄ and the organic layer was concentrated under reduced pressure to give a residue (40 mg) as a yellow solid: LC-MS (ESI ⁺ ) m/z 433.1 (M+H) ⁺ .

1-(3,6,9,12-Tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid (Intermediate CI)

Step 1 - 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-methyl carboxylate and 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-3-carboxylate. To a solution of 3,6,9,12-tetraoxapentadeca-14-yn-1-yl 4-methylbenzenesulfonate (4.2 g, 10.87 mmol, synthesized by step 1 of intermediate BK) and methyl 1H-pyrazole-5-carboxylate (1.37 g, 10.9 mmol) in DMF (60 mL) was added KI (180 mg, 1.09 mmol) and _Cs2CO3 (7.08 g, 21.7 mmol) in one portion. The resulting mixture was stirred at 70°C for ₂ h. Upon completion, the reaction mixture was quenched with _H2O (60 mL) at 20°C and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (60 mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a _residue . The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give methyl 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-5-carboxylate (1.2 g, 32% yield, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.58 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.66 (t, J = 5.6 Hz, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.83 (s, 3H), 3.74 (t, J = 5.6 Hz, 2H), 3.55 - 3.50 (m, 4H), 3.47 - 3.41 (m, 9H)) and methyl 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-3-carboxylate (1.5 g, 41% yield, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.02 (d, J = 2.4 Hz, 1H), 5.90 (d, J = 2.4 Hz, 1H), 3.51 (t, J = 5.2 Hz, 2H), 2.99 - 2.93 (m, 5H), 2.73 - 2.61 (m, 13H), 2.50 (s, 2H)) as a yellow gum.

Step 2 - 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid. A solution of methyl 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-5-carboxylate (1.2 g, 3.53 mmol) and ^LiOH.H ₂ O (591 mg, 14.1 mmol) in THF (10 mL) and H ₂ O (5 mL) was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (20 mL×3). The aqueous phase was then adjusted to pH=3-4 and extracted with EtOAc mL (20 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure to give the title compound (700 mg) as a yellow gum: LC-MS (ESI ⁺ ) m/z 327.2 (M+H) ⁺ .

(1R,3S)-3-(5-(1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate CJ)

A solution of 1-(3,6,9,12-tetraoxapentadec-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.23 mmol, intermediate CI), (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (455 mg, 1.48 mmol, intermediate U), DIEA (318 mg, 2.46 mmol), _T3P (2.35 g, 3.69 mmol, 50% solution in DMF) in MeCN (10 mL) was stirred at 80° C. for 12 h. On completion, the mixture was quenched with _NH4Cl (sat. aq, 10 mL) and extracted with EtOAc (20 ml×2). The combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , PE:EtOAc=0:1) to give the title compound (490 mg, 64% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 617.4 (M+H) ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ = 8.10 (br s, 1H), 7.55 (s, 1H), 6.66 (br s, 1H), 6.21 (s, 1H), 5.15 (br s, 1H), 4.77 (t, J = 5.2 Hz, 2H), 4.66 - 4.52 (m, 1H), 4.17 (d, J = 2.4 Hz, 2H), 3.88 (t, J = 5.2 Hz, 2H), 3.85 - 3.76 (m, 1H), 3.68 - 3.62 (m, 4H), 3.59 - 3.54 (m, 4H), 3.52 - 3.47 (m, 4H), 3.17 - 3.07 (m, 1H), 2.52 - 2.45 (m, 1H), 2.43 (t, J = 2.4 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.98 - 1.92 (m, 1H), 1.89 - 1.84 (m, 2H), 1.65 (s, 9H), 1.62 (br d, J = 6.4 Hz, 2H), 1.17 - 1.13 (m, 6H).

(1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate (Intermediate CK)

Step 1 - (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate. To a solution of (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (500 mg, 956 umol, from the synthesis of intermediate U according to step 1) and pyrrolidine (136 mg, 1.91 mmol) in THF (5 mL) was added DIEA (618 mg, 4.78 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with H ₂ O (8 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine ( ₁₀ mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 3/1 to 2/1) to give the title compound (360 mg, 791 umol, 83% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 455.2 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate. To a solution of (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate (360 mg, 791 umol) in THF (4 mL) was added Pd/C (30 mg, 28.3 umol, 10 wt%) in one portion. The mixture was stirred at 25 °C under _H2 atmosphere (15 psi) for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (250 mg, 780 umol, 99% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 321.5 (M+H) ⁺ .

Pyrrolidine-1-carboxylate (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl (Intermediate CL)

To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate (250 mg, 780 umol, intermediate CK) and 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid (210 mg, 743 umol, intermediate BE) in ACN (2 mL) was added _T3P (1.42 g, 2.23 mmol, 50% solution in DMF) and DIEA (480 mg, 3.72 mmol) in one portion. The mixture was stirred at 60° C. for 12 h. The reaction mixture was quenched with _H2O (3 mL) at 25° C. and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine ( ₅ mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, gradient elution of 0-100% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound as an orange solid. LC-MS (ESI ⁺ ) m/z 385.5 (M+H) ⁺ .

3-(Methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (Intermediate CM)

Step 1 - Ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate. To a solution of 3-methylprop-1-yne (10.2 g, 145 mmol, CAS#627-41-8) in toluene (80 mL) was added ethyl 2-diazoacetate (18.2 g, 160 mmol). The mixture was stirred at 110° C. for 6 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (10 g, 37% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.71 (s, 1H), 6.81 (s, 1H), 4.67 (s, 1H), 4.55 (s, 2H), 4.40 (q, J = 7.2 Hz, 3H), 3.44 (s, 1H), 3.41 (s, 3H), 1.43 (s, 1H), 1.42 - 1.38 (m, 3H).

Step 2 - Ethyl 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate and ethyl 5-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate. A solution of ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate (2.50 g, 13.6 mmol), 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (3.87 g, 11.3 mmol, synthesized by step 1 of intermediate BE), Cs ₂ CO ₃ (18.4 g, 56.5 mmol), KI (187 mg, 1.13 mmol) in DMF (80 mL) was stirred at 70° C. for 12 h. Upon completion, the mixture was quenched with NH ₄ Cl (sat. aq, 80 mL) and extracted with EtOAc (8 mL×3). The combined organic layers were washed with brine (80 mL×3), dried over Na ₂ SO ₄ and concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1-3/1) to give ethyl 5-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate (1.50 g, 34% yield) as a colorless oil ( ¹ H NMR (400 MHz, CD ₃ Cl) δ 6.74 (s, 1H), 6.54 (s, 2H), 6.43- 6.39 (m, 5H), 4.20 (d, J = 2.4 Hz, 2H), 3.87 (t, J = 6.0 Hz, 3H), 3.67 - 3.53 (m, 8H), 3.34(s, 3H), 2.44 (t, J = 2.0 Hz, 1H), 1.39 (t, J = 7.2 Hz, 4H); LC-MS(ESI ⁺ )m/z 355.2(M+H) ⁺ ), and ethyl 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (0.68 g, 15% yield) ( ¹ H NMR (400 MHz, CD ₃ Cl) δ 6.84 (s, 1H), 4.75 (t, J = 6.0 Hz, 2H), 4.46 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 4.20 (d, J = 2.4 Hz, 2H), 3.86 (t, J = 6.0 Hz, 3H), 3.73 - 3.55 (m, 12H), 3.40 (s, 3H), 2.43 (t, J = 2.0 Hz, 1H), 1.37 (t, J = 7.2 Hz, 4H); LC-MS (ESI ⁺ ) m/z 355.2 (M+H) ⁺ ) was obtained.

step 3 - 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid. A solution of ethyl 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (1.50 g, 4.23 mmol), ^LiOH.H2O ( ₈₈₈ mg, 21.2 mmol) in THF (10 mL) and _H2O (5 mL) was stirred at 40 °C for 4 h. On completion, the mixture was quenched with _NH4Cl (sat. aq, 20 mL) and then extracted with EtOAc (20 mL x 2). The aqueous layer was acidified with HCl/1M (10 mL) to pH<4 and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (80 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuo. ¹ H NMR (400 MHz, CD ₃ Cl) δ = 6.90 (s, 1H), 4.77 (t, J = 5.6 Hz, 2H), 4.48 (s, 2H), 4.21 (d, J = 2.4 Hz, 3H), 3.85 (t, J = 5.6 Hz, 3H), 3.72 - 3.58 (m, 11H), 3.40 (s, 3H); LC-MS(ESI ⁺ )m/z 327.2(M+H) ⁺ .

(1R,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate CN)

A solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (472 mg, 1.53 mmol, Intermediate U), 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (500 mg, 1.53 mmol, Intermediate CM), _T3P (2.92 g, 4.60 mmol, 50% solution in DMF), DIEA (990 mg, 7.66 mmol) in ACN (10 mL) was stirred at 60° C. for 12 h. Upon completion, the mixture was quenched with _H2O (10 mL) and then extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 Ml x 3), dried over _Na2SO4 and concentrated in vacuum. The residue was purified by prep-TLC ( _SiO2 , EtOAc:PE=2:1) to give the title compound (600 _mg , yield 57%) as a yellow oil. ^1H NMR (400 MHz, _CD3Cl ) δ 8.26 - 8.19 (m, 1H), 6.65 (s, 1H), 6.32 (s, 1H), 5.19 - 5.15 (m, 1H), 4.74 - 4.71 (m, 2H), 4.50 (s, 2H), 4.15 (d, J = 1.6 Hz, 2H), 4.14 (br s, 1H), 3.84 (br t, J = 4.8 Hz, 2H), 3.59 (br d, J = 4.8 Hz, 2H), 3.58 - 3.53 (m, 3H), 3.49 (br d, J = 4.4 Hz, 4H), 3.44 (br s, 1H), 3.44 (s, 3H), 2.44 (br d, J = 2.0 Hz, 1H), 2.05 (s, 2H), 1.73 (s, 9H), 1.27 (s, 3H), 1.15 (br d, J = 6.4 Hz, 6H). LC-MS(ESI ⁺ )m/z 617.4(M+H) ⁺ .

4-((6-bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (intermediate CO)

Step 1 - Ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate. To a solution of ethyl 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (10 g, 42.9 mmol, CAS# 1074-68-6) in dioxane (100 mL) was added TEA (8.70 g, 85.9 mmol) and cyclopentanamine (4.39 g, 51.5 mmol, CAS# 1003-03-08). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (100 mL) at 25 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 _mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (11.5 g, 40.8 mmol, 95% yield) as an orange oil. LC-MS (ESI ⁺ ) m/z 272.2 (M+H) ⁺ .

Step 2 - (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol. To a solution of ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (11.5 g, 40.8 mmol) in DCM (130 mL) at -65 °C was added DIBAL-H (1 M, 61.31 mL) dropwise and stirred at -50 to 55 °C under _N2 atmosphere for 3 h. Upon completion, the reaction mixture was quenched with MeOH (120 mL) at -65 °C, then diluted with _DCM (120 mL) and extracted with DCM (120 mL x 3). The combined organic layers were washed with brine (120 mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-100% ethyl acetate/petroleum ether at 100 mL/min) to give the title compound (5.5 g, 22.9 mmol, 56% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 240 (M+H) ⁺ .

Step 3 - 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde. To a solution of (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (2 g, 4.18 mmol) in EtOAc (50 mL) was added MnO ₂ (14.5 g, 83.5 mmol). The mixture was stirred at 50° C. under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title (1.5 g) as an orange oil. LC-MS (ESI ⁺ ) m/z 238.1 (M+H) ⁺ .

Step 4 - 8-Cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. A solution of 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (3.8 g, 16.0 mmol) and ethyl acetate (4.23 g, 48.0 mmol) in THF (45 mL) was purged with nitrogen and cooled to an internal temperature of -5 °C in a MeOH-ice bath. LiHMDS (1 M, 48.04 mL) was then added slowly enough to maintain the internal temperature at -5 °C. This mixture was then stirred at 0-20 °C under a _N2 atmosphere for 12 hours. The resulting red solution was cooled to internal -3 °C in an ice-water bath, then EtOH (45 mL) was added via cannula slowly enough to maintain the internal temperature at -3 °C. The mixture was stirred in an ice bath for 1 h, then the cooling bath was removed, the solution was allowed to warm to internal 20° C., and stirring was continued for 1 h. The solvent was evaporated, the residue was diluted with water (45 mL) and brine (50 mL×3), and the aqueous layer was extracted with EtOAc (20 mL, then 45 mL×2). The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (3 g, 11.4 mmol, 72% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 262.2 (M+H) ⁺ .

Step 5 - 6-Bromo-8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3 g, 11.4 mmol) in DMF (30 mL) was added NBS (2.25 g, 12.6 mmol). The mixture was then stirred at 20°C for 12 h. The reaction mixture was quenched with water (30 mL) at 25° _C and then extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 3/1) to give the title compound (1 g, 2.94 mmol, 26% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 342.1 (M+H) ⁺ .

Step 6 - 6-Bromo-8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-bromo-8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1 g, 2.94 mmol) in THF (20 mL) and H ₂ O (20 mL) was added oxone (4.52 g, 7.35 mmol) in one portion. The mixture was stirred at 30°C for 3 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (900 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 373.9 (M+H) ⁺ .

Step 7 - 2-((4-(benzylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-bromo-8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (900 mg, 2.42 mmol) and 4-benzylsulfanyl-2-methyl-aniline (554 mg, 2.42 mmol, intermediate M) in IPA (10 mL) was added TFA (5.51 g, 48.36 mmol). The mixture was stirred at 120 °C for 24 h. Upon completion, the reaction mixture was quenched with water (10 mL) at 25 °C and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 14 g SepaFlash® silica flash column, gradient elution of 0-100% ethyl acetate/petroleum ether at 100 mL/min) to give the title compound (300 mg, 575 umol, 24% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 523 (M+H) ⁺ .

Step 8 - 4-((6-Bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride. To a solution of 2-((4-(benzylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one (300 mg, 575 umol) in HCl (1.5 mL) and AcOH (5 mL) was added NCS (307 mg, 2.30 mmol) at 0° C. The mixture was stirred at 0-25° C. for 2 h. Upon completion, the reaction mixture was quenched with water (10 mL) at 25° C. and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (280 mg) as an orange solid: LC-MS (ESI ⁺ ) m/z 373.9 (M+H) ⁺ .

3-(5-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate CP)

Step 1 - (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)benzyl carbamate. To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethanamine (1 g, 5.34 mmol CAS# 932741-19-0) in DCM (15 mL) was added TEA (594 mg, 5.87 mmol) in one portion and then benzyl carbonochloridate (1.00 g, 5.87 mmol) was added to the mixture at 0° C. The mixture was stirred at 0-20° C. for 12 hours. Upon completion, the mixture was poured into ice water (20 mL) and extracted with DCM (20 mL×2). The combined organic phase was washed with brine (20 mL×2) and dried over sodium sulfate. Then it was filtered to get the filtrate and concentrated to get a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/1) to give the title compound (1.29 g, 3.83 mmol, 72% yield) as a yellow oil. LC-MS (ESI+) m/z 322.1 (M+H) ⁺ .

Step 2 - (2-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)benzyl carbamate. To a solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.04 g, 6.02 mmol, intermediate J) and (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)benzylcarbamate (1.29 g, 4.01 mmol) in THF (7 _mL ) and ACN (7 mL) was added _Cs2CO3 (7.85 g, 24.08 mmol) and XPhos Pd G3 (1.02 g, 1.20 mmol) in one portion. The mixture was then degassed with nitrogen and heated to 60 °C, then stirred for 10 h. Upon completion, the mixture was poured into ice water (10 mL) and extracted with EA (2 x 10 mL). The combined organic phase was washed with brine (2×10 mL) and dried over sodium sulfate. The solution was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/4) to give the title compound (1.3 g, 2.04 mmol, 51% yield) as a yellow oil. LC-MS (ESI+) m/z 840.3 (M+H) ⁺ .

Step 3: 3-(5-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. To a solution of (2-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)benzyl carbamate (1.3 g, 2.25 mmol) in THF (10 mL) was added Pd/C (0.2 g, 188.68 umol, 10 wt %) at 20° C. The mixture was then stirred under a hydrogen atmosphere (15 psi) for 13 hours at 20° C. Upon completion, the mixture was filtered and the filtrate was concentrated to give the title compound (850 mg) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.05 - 6.98 (m, 2H), 6.89 - 6.85 (m, 1H), 5.33 (dd, J = 5.2, 12.8 Hz, 1H), 3.61 - 3.59 (m, 1H), 3.55 - 3.48 (m, 8H), 3.42 - 3.35 (m, 6H), 3.18 - 3.05 (m, 1H), 2.95 - 2.82 (m, 1H), 2.76 - 2.56 (m, 6H), 1.86 - 1.72 (m, 4H).

(1S,3R)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate CQ)

A solution of 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.42 mmol, intermediate BE), (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (743 mg, 2.41 mmol, intermediate CB), _T3P (2.71 g, 4.25 mmol, 50% solution in DMF), DIEA (366 mg, 2.83 mmol) in ACN (8 mL) was stirred at 60° C. for 16 h. Upon completion, the mixture was quenched with _NH4Cl (sat. aq, 10 mL) and then extracted with EtOAc (10 mL×2). _The combined organic layers were washed with brine (10 mL x 3), dried over _Na2SO4 and concentrated in vacuo. The crude product was purified by reverse phase (0.1% FA condition) to give the title compound (100 mg, 12% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 573.8 (M+H) ⁺ .

3-[(4-Methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (Intermediate CR)

To a solution of hexahydropyrimidine-2,4-dione (3.00 g, 26.2 mmol, CAS#504-07-4) in DMF (60 mL) was added Cs ₂ CO ₃ (17.13 g, 52.58 mmol) at room temperature. Then the mixture was warmed to 50° C. and PMB-Cl (3.71 g, 23.6 mmol) was added dropwise to the mixture at 50° C. very slowly. The mixture was stirred at 50° C. for 2 h. Upon completion, the reaction was cooled to room temperature. The reaction was filtered and the filter cake was washed with EA (30 mL×2), the filtrate was poured into water (150 mL) and extracted with EA (100 mL×2). The combined organic layer was washed with water (100 mL) and saturated brine (100 mL), then the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was suspended in EA/PE (1/1, 80 mL) and stirred for 0.5 h. The suspension was filtered and the filter cake was dried to give the title compound (2.80 g, 45% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 - 7.30 (m, 2H), 6.90 - 6.62 (m, 2H), 6.15 (s, 1H), 4.88 (s, 2H), 3.78 (s, 3H), 3.37 (dt, J = 2.4, 6.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H).

3-(4-Methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate CS)

To a mixture of dihydropyrimidine-2,4(1H,3H)-dione (10.0 g, 87.6 mmol, CAS#504-07-4) in DMF (100 mL) was added PMB-Cl (13.7 g, 87.6 mmol, 11.9 mL), Cs ₂ CO ₃ (28.5 g, 87.6 mmol) at 25° C. The mixture was then stirred at 50° C. for 3 h. Upon completion, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum. The crude product was purified by recrystallization from EA/PE (20 mL, v/v=1/1) at 25° C. to give the title compound (9.40 g, 45% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.81 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.72 (s, 2H), 3.72 (s, 3H), 3.23 - 3.20 (m, 2H), 2.63 (t, J = 6.8 Hz, 2H).

4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexanol (Intermediate CT)

Step 1 - 4-(hydroxymethyl)cyclohexanol

To a solution of LiAlH ₄ (3.31 g, 87.1 mmol) in THF (30 mL) was added ethyl 4-hydroxycyclohexanecarboxylate (10.0 g, 58.0 mmol, CAS#3618-04-0) in THF (100 mL) dropwise at 0° C., then the mixture was stirred at 0° C. for 5 h. Upon completion, the mixture was quenched with H ₂ O (3.3 mL) and then a solution of 15% NaOH (3.3 mL) was added dropwise. The mixture was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo to give the title compound (7.5 g, 99% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 3.37 - 3.23 (m, 1H), 3.17 (d, J = 6.0 Hz, 2H), 1.85 - 1.75 (m, 2H), 1.75 - 1.62 (m, 2H), 1.30 - 1.16 (m, 1H), 1.14 - 0.95 (m, 2H), 0.93 - 0.72 (m, 2H).

Step 2 - 4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexanol

To a solution of 4-(hydroxymethyl)cyclohexanol (6.5 g, 49.9 mmol) and imidazole (4.08 g, 59.9 mmol) in DMF (200 mL) was added TBDPSCl (14.4 g, 52.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. Upon completion, the mixture was diluted with H ₂ O (100 mL) and extracted with EA (2 x 30 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The mixture was purified by silica gel column (PE:EA = 5:1) to give the title compound (9.10 g, yield 49%) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.70 - 7.60 (m, 4H), 7.48 - 7.31 (m, 6H), 3.63 - 3.51 (m, 1H), 3.47 (d, J = 6.0 Hz, 2H), 2.05 - 1.95 (m, 2H), 1.89 - 1.80 (m, 2H), 1.50 - 1.45 (m, 1H), 1.31 - 1.22 (m, 2H), 1.10 - 1.00 (m, 2H), 1.05 (s, 9H).

(4-Allyloxycyclohexyl)methoxy-tert-butyl-diphenyl-silane (Intermediate CU)

To a solution of 4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexanol (500 mg, 1.36 mmol, intermediate CT) in THF (5 mL) was added NaH (81.3 mg, 2.03 mmol, 60% dispersion in mineral oil) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, then 3-bromoprop-1-ene (656 mg, 5.43 mmol, 0.3 mL, CAS#106-95-6) was added dropwise. The mixture was stirred at 25 °C for 4 h. Upon completion, the mixture was quenched with H ₂ O (1 mL) at 25 °C, diluted with H ₂ O (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH=10:1) to give the title compound (210 mg, yield 37%) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.59 - 7.55 (m, 4H), 7.33 - 7.26 (m, 6H), 5.91 - 5.78 (m, 1H), 5.22 - 5.13 (m, 1H), 5.10 - 5.02 (m, 1H), 3.98 - 3.89 (m, 2H), 3.37 (d, J = 6.4 Hz, 2H), 3.18 - 3.08 (m, 1H), 2.01 - 1.95 (m, 2H), 1.79 - 1.73 (m, 2H), 1.45 - 1.41 (m, 1H), 0.96 (s, 9H), 0.93 - 0.88 (m, 2H), 0.80 - 0.76 (m, 2H).

N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-cyclopentyl-pyrimidine-2,4-diamine (Intermediate CV)

Step 1 - 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloro-pyrimidine (10 g, 43.8 mmol, CAS#36082-50-5) in dioxane (100 mL) was added cyclopentanamine (4.48 g, 52.6 mmol, CAS#1003-03-8) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 6 hours. Upon completion, the reaction was poured into ice water (100 mL) and then extracted with ethyl acetate (150 mL×2). The combined organic layers were washed with brine (70 mL×2), dried over sodium sulfate, and then filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (4.7 g, 38% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.10 (s, 1H), 5.45 (br s, 1H), 4.57 - 4.29 (m, 1H), 2.20 - 2.08 (m, 2H), 1.82 - 1.57 (m, 4H), 1.48 (qd, J = 6.4, 12.8 Hz, 2H).

Step 2: N2-(4-(benzylthio)-2-methylphenyl)-5-bromo-N4-cyclopentylpyrimidine-2,4-diamine

To a solution of 5-bromo-2-chloro-N-cyclopentyl-pyrimidin-4-amine (2.65 g, 9.59 mmol) in isopropanol (40 mL) was added 4-benzylsulfanyl-2-methyl-aniline (2 g, 8.72 mmol, intermediate DE) and TFA (19.8 g, 174 mmol) at 20° C. under nitrogen flow. The reaction was then stirred at 80° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (40 mL) and extracted with EtOAc (50 mL×2). The combined organic layers are washed with brine (30 mL×2) and dried over sodium sulfate. The mixture was then filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (3.4 g, 83.0% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 11.05 (s, 1H), 7.80 (s, 1H), 7.35 - 7.23 (m, 6H), 7.20 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 2.0, 8.3 Hz, 1H), 5.99 (br d, J = 6.8 Hz, 1H), 4.18 - 4.06 (m, 3H), 2.28 (s, 3H), 2.00 - 1.85 (m, 2H), 1.79 - 1.56 (m, 4H), 1.52 - 1.44 (m, 2H).

4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate CW) and 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (Intermediate FX).

Step 1 - (E)-3-[2-(4-benzylsulfanyl-2-methyl-anilino)-4-(cyclopentylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester

A mixture of N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-cyclopentyl-pyrimidine-2,4-diamine (10 g, 21.3 mmol, intermediate CV), methyl prop-2-enoate (12.6 g, 146 mmol, CAS#96-33-3), TEA (6.47 g, 63.9 mmol), and Pd( _PPh3 ) ₄ (2.46 g, 2.13 mmol) in DMF (200 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 90 °C under _N2 atmosphere for 36 h. Upon completion, the reaction mixture was quenched with _H2O (100 mL) at 25 °C and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (FA conditions) to give the title compound (15.6 g, 70% yield). ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.50 (s, 1H), 8.32 (s, 1H), 7.82 (d, J = 15.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.34 - 7.30 (m, 3H), 7.29 - 7.25 (m, 3H), 7.18 (s, 1H), 7.11 (dd, J = 1.6, 8.4 Hz, 1H), 6.31 (d, J = 15.6 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.18 (s, 2H), 3.69 (s, 3H), 2.19 (s, 3H), 1.88 - 1.82 (m, 2H), 1.70 - 1.66 (m, 2H), 1.52 - 1.46 (m, 4H). LC-MS(ESI ⁺ )m/z 475.2(M+H) ⁺ .

Step 2 - 2-(4-benzylsulfanyl-2-methyl-anilino)-8-cyclopentyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of methyl (E)-3-[2-(4-benzylsulfanyl-2-methyl-anilino)-4-(cyclopentylamino)pyrimidin-5-yl]prop-2-enoate (7.8 g, 16.4 mmol) in DMF (80 mL) was added t-BuOK (5.53 g, 49.3 mmol). The mixture was stirred at 25 °C for 30 min. The mixture was then heated to 120 °C and stirred for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (200 mL) and extracted with EA (2 x 300 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=40/1 to 10/1, Rf=0.24) to give the title compound (4.60 g, 63% yield) as a yellow solid: LC-MS (ESI ⁺ ) m/z 443.0 (M+H) ⁺ .

Step 3 - 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride and 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-8-cyclopentyl-pyrido[2,3-d]pyrimidin-7-one (2 g, 4.52 mmol) in ACN (20 mL), AcOH (2 mL), and H ₂ O (0.5 mL) was added NCS (2.41 g, 18 mmol) in the dark. The mixture was stirred at 25° C. in the dark for 0.5 h. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=40/1-10/1, Rf=0.40) to give 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (1.49 g, 72% yield) as a yellow solid ( ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 7.50 (s, 1H), 7.45 - 7.35 (m, 2H), 5.71 (s, 1H), 2.22 (s, 3H), 2.15 - 2.04 (m, 2H), 1.69 (s, 4H), 1.44 (s, 2H)) and 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (0.25 g, 12% yield) as a yellowish solid ( ¹ H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.60 (s, 1H), 8.04 - 7.86 (m, 2H), 7.79 (s, 1H), 7.42 (s, 1H), 5.94 (quin, J = 8.7 Hz, 1H), 2.51 (s, 3H), 2.43 - 2.22 (m, 2H), 2.18 - 2.06 (m, 2H), 2.00 - 1.85 (m, 2H), 1.81 - 1.56 (m, 3H); LC-MS (ESI+) m/z 419.1 (M+H) ⁺ ).

[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (intermediate CY)

Step 1 - 5-oxotetrahydrofuran-2-carboxylic acid

To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS#617-65-2) in H ₂ O (800 mL) and HCl (12 M, 210 mL) was added a solution of NaNO ₂ (147 g, 2.13 mol) in H ₂ O (400 mL) at −5° C. The mixture was stirred at 15° C. for 12 h. Upon completion, the mixture was concentrated, then dissolved in EA (500 mL) and filtered and washed with EA (3×100 mL). The filtrate and washing solution were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (200 g, crude) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 6.43 (s, 1H), 5.02 - 4.95 (m, 1H), 2.67 - 2.38 (m, 4H).

Step 2 - N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide

To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was added SOCl ₂ (246 g, 2.07 mol) slowly at 0 °C. The mixture was stirred at 85 °C for 3 h, then the mixture was stirred at 15 °C for 6 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (1 L) at 0 °C under N _2. Then, a solution of Et ₃ N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, then the mixture was stirred at 15 °C for 3 h. Upon completion, water (600 mL) was added and the mixture was extracted with DCM (3 x 300 mL). The combined organic phase was washed with 0.5 M HCl (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.22 - 7.20 (d, J = 8.0, 1H), 6.89 - 6.87 (d, J = 8.0, 1H), 4.90 - 4.86 (m, 1H), 4.47 - 4.4.36 (m, 2H) 3.81 (s, 3H), 2.67 - 2.64 (m, 1H), 2.59 - 2.54 (m, 2H), 2.40 - 2.38 (m, 1H); LC-MS(ESI ⁺ )m/z 272.0(M+Na) ⁺ .

Step 3 - 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

A solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to −78° C. Then, t-BuOK (62.7 g, 559 mmol) in a solution of anhydrous THF (1000 mL) was slowly added dropwise at −78° C. under nitrogen atmosphere. The resulting reaction mixture was stirred at −40° C. for 1 h. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl solution (100 mL). The mixture was extracted with ethyl acetate (3×1500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (PE:EA=1:1) to give the title compound (128 g, 92% yield) as a white solid. ^1H NMR (400MHz, _CDCl3 ) δ 7.39 - 7.32 (m, 2H), 6.89 - 6.81 (m, 2H), 4.91 (s, 2H), 4.17 - 4.11 (m, 1H), 3.80 (s, 3H), 3.54 (s, 1H), 2.98 - 2.87 (m, 1H), 2.73 - 2.60 (m, 1H), 2.26 - 2.20 (m, 1H), 1.80 (dq, J = 4.8, 13.1 Hz, 1H).

Step 4 - [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] = trifluoromethanesulfonate

To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethanesulfonyl trifluoromethanesulfonate (73.0 g, 258 mmol) dropwise at 0 °C. The mixture was stirred at -10 °C under _N2 for 1.5 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA = 20:1/8:1) to afford the title compound (45.0 g, 68% yield) as a pale yellow gum. ^1H NMR (400MHz, _CDCl3 ) δ 7.36 (d, J = 8.4 Hz, 2H), 6.85 - 6.82 (m, 2H), 5.32 - 5.28 (m, 1H), 4.91 (s, 2H), 3.79 (s, 3H), 3.02 - 2.97 (m, 1H), 2.79 - 2.74 (m, 1H), 2.41 - 2.35 (m, 2H).

5-Bromo-3-methyl-1H-benzimidazol-2-one (Intermediate CZ)

Step 1 - 5-bromo-N-methyl-2-nitro-aniline

4-Bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS#321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15° C. for 10 min. Upon completion, the mixture was diluted with H ₂ O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H).

Step 2 - 4-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 5-bromo-N-methyl-2-nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and H ₂ O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50° C., and then Fe (174 g, 3.11 mol) was added to the reaction mixture. The reaction mixture was then stirred at 80° C. for 6 h. Upon completion, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was diluted with H ₂ O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with aq. NaHCO ₃ and brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as a black oil. ^1H NMR (400MHz, DMSO- _d6 ) δ 6.55 - 6.52 (m, 1H), 6.48 - 6.45 (m, 1H), 6.43 - 6.42 (m, 1H), 4.89 - 4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d, J = 4.0 Hz, 3H).

Step 3 - 5-bromo-3-methyl-1H-benzimidazol-2-one

To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol) in CH ₃ CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture was stirred at 80 °C under N ₂ for 6 h. Upon completion, the mixture was concentrated in vacuum. The mixture was diluted with H ₂ O (1.0 L) and filtered. The filter cake was washed with water (3 x 200 mL) and dried in vacuum to give the title compound (106 g, 85% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.00 (s, 1H), 7.33 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H).

3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (Intermediate DA)

Step 1 - 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6 mmol, Intermediate CZ) in THF (300 mL) was added t-BuOK (3.63 g, 32.3 mmol) at 0° C. The mixture was stirred at 0-10° C. under N ₂ for 1 h. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (9.87 g, 25.9 mmol, Intermediate CY) in THF (100 mL) was added to the reaction mixture over 30 min at 0-10° C. The mixture was stirred at 0-10° C. under N ₂ for 30 min. An additional solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (2.47 g, 6.47 mmol) in THF (20 mL) was added dropwise to the reaction mixture at 0-10° C. Then the mixture was stirred at 0-10° C. under N ₂ for another 30 min. Upon completion, the reaction was quenched with water (400 mL) and extracted with EA (3×200 mL). The combined organic layers were concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound (6.70 g, 67% yield) as a pale yellow solid. The filtrate was also concentrated in vacuo and the residue was purified by column chromatography to give another batch of the title compound (1.80 g, 18% yield) as a pale yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 7.47 (d, J = 1.6 Hz, 1H), 7.21 - 7.16 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 5.55 - 5.51 (m, 1H), 4.84 - 4.73 (m, 2H), 3.72 (s, 3H), 3.33 (s, 3H), 3.04 - 3.00 (m, 1H), 2.83 - 2.67 (m, 2H), 2.07 - 2.05 (m, 1H).

Step 2 - 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was added methanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15 °C). The mixture was stirred at 120 °C for 2 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was poured into ice/water (200 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over _{Na2SO4 ,} filtered and concentrated in vacuum. The residue was triturated with EA (80 mL) and filtered. The filtrate cake was collected and dried in vacuum to give the title compound (4.20 g, 67% yield) as an off-white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 5.40 - 5.35 (m, 1H), 2.34 (s, 3H), 2.92 - 2.88 (m, 1H), 2.71 - 2.60 (m, 2H), 2.03 - 1.99 (m, 1H).

3-[3-Methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (Intermediate DB)

Step 1 - 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate tert-butyl

A solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (5.00 g, 14.8 mmol, intermediate DA), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.49 g, 17.7 mmol, CAS# 286961-14-6), K ₃ PO ₄ (6.28 g, 29.6 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.16 g, 1.48 mmol) in dioxane (100 mL) and H ₂ O (5.0 mL) was stirred at 80° C. for 4 hours. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo The residue was purified by reverse phase flash (0.1% FA condition) to give the title compound (2.30 g, 53% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.27 (s, 1H), 7.14 - 7.04 (m, 2H), 6.11 (s, 1H), 5.36 (dd, J = 12.8, 5.2 Hz, 1H), 4.01 (d, J = 7.2 Hz, 2H), 3.55 (t, J = 5.6 Hz, 2H), 3.35 (s, 3H), 2.95 - 2.83 (m, 1H), 2.73 - 2.59 (m, 2H), 2.06 - 1.95 (m, 2H),1.46 - 1.39 (m, 9H), 1.17 (t, J = 7.2 Hz, 1H). LC-MS(ESI ⁺ )m/z 441.2(M+H) ⁺ .

Step 2 - 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.30 g, 5.22 mmol) in THF (150 mL) was added Pd/C (800 mg, 10 wt%) and Pd(OH) ₂ (800 mg, 5.70 mmol) at 25° C. The reaction mixture was stirred at 60° C. under H ₂ (15 psi) for 16 h. Upon completion, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound (2.30 g, 87% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.10 (s, 1H), 7.02 - 6.87 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 5.23 (dd, J = 5.6, 12.6 Hz, 1H), 4.30 - 4.25 (m, 2H), 3.45 (s, 3H), 2.99 - 2.68 (m, 6H), 2.30 - 2.21 (m, 1H), 1.88 - 1.81 (m, 2H), 1.51 (s, 9H), 1.48 - 1.44 (m, 2H). LC-MS(ESI ⁺ )m/z 465.2(M+23) ⁺ .

Step 3 - 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (300 mg, 678 umol) in DCM (3.0 mL) was added HCl/dioxane (4 M, 170 uL) in one portion at 25° C. under N ₂ . The mixture was stirred at 25° C. for 30 min. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (250 mg, 91% yield, HCl salt) as a white solid. LC-MS (ESI ⁺ ) m/z 343.1 (M+H) ⁺ .

3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate DC)

Step 1 - 2-Bromo-N-methyl-6-nitro-aniline

To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS#58534-94-4) in THF (40 mL) was added MeNH ₂ (2M, 400 mL). The reaction mixture was stirred at 60° C. for 12 h. Upon completion, the reaction mixture was poured into sat. NaHCO ₃ (30 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (40.0 g, 95% yield) as a red oil. LC-MS (ESI ⁺ ) m/z 230.9 (M+H) ⁺ .

Step 2 - 3-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 2-bromo-N-methyl-6-nitro-aniline (23.0 g, 99.5 mmol) in EA (300 mL) and H ₂ O (10 mL) was added AcOH (100 mL). The mixture was warmed to 50° C. Then Fe (22.2 g, 398 mmol) was added to the reaction mixture and the mixture was heated to 80° C. for about 4 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EA (3×200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (20.0 g, 99% yield) as a red oil. ^1H NMR (400MHz, DMSO- _d6 ) δ 6.73 - 6.70 (m, 1H), 6.68 - 6.60 (m, 2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58 (s, 3H).

Step 3 - 4-Bromo-3-methyl-1H-benzimidazol-2-one

To a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4 mmol) in ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reaction mixture was stirred at 85 °C under _N2 atmosphere for 12 h. Upon completion, the reaction mixture was concentrated in vacuum. The reaction mixture was diluted with water (200 mL) and a solid precipitate formed which was filtered off. The solid was washed with water (1 L) and dried in vacuum to give the title compound (20.0 g, 88% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.17 (s, 1H), 7.14 (dd, J = 1.2, 8.0 Hz, 1H), 7.00 - 6.95 (m, 1H), 6.93 - 6.87 (m, 1H), 3.55 (s, 3H).

Step 4 - 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8 mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. Then, [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (20.1 g, 52.8 mmol, intermediate CY) in a solution of THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at 20 °C under N ₂ for 0.5 h. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in reduced pressure. The crude product was purified by reverse-phase HPLC (0.1% FA) to give the title compound (13.3 g, 55% yield) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ 7.38 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.80 (t, J = 8.0 Hz, 1H), 6.48 - 6.40 (d, J = 8.0 Hz, 1H), 5.22 (dd, J = 5.2, 12.8 Hz, 1H), 5.04 - 4.93 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.12 - 2.98 (m, 1H), 2.93 - 2.77 (m, 1H), 2.62 (dq, J = 4.4, 13.2 Hz, 1H), 2.20 - 2.17 (m, 1H).

Step 5 - 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with _N2 three times, then the mixture was stirred at 120 °C under _N2 atmosphere for 2 h. Upon completion, the reaction mixture was concentrated in vacuum to remove toluene. To the residue was added 200 mL of ice water, then a white solid precipitate formed. The mixture was filtered, and the filter cake was collected and dried in vacuum to give the title compound (7.30 g, 74% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.13 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.05 - 6.93 (m, 1H), 5.41 (dd, J = 5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 2.96 - 2.83 (m, 1H), 2.78 - 2.59 (m, 2H), 2.08 - 2.00 (m, 1H).

3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate DD)

Step 1 - 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (1.00 g, 2.18 mmol, synthesized by steps 1-4 of Intermediate DC) and tert-butyl-3,9-diazaspiro[5.5]undecane-3-carboxylate (666 mg, 2.62 mmol, CAS# 173405-78-2) in dioxane (15 mL) was added Pd-PEPPSI-IHEPTCl 3-chloropyridine (212 mg, 218 umol) and Cs ₂ CO ₃ (1.42 g, 4.36 mmol). The mixture was then stirred at 100° C. for 10 hours. Upon completion, the mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (400 mg, 29% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 -d) δ 7.40 - 7.35 (m, 2H), 6.93 - 6.86 (m, 2H), 6.86 - 6.80 (m, 2H), 6.28 (d, J = 7.2 Hz, 1H), 5.21 (dd, J = 5.4, 13.0 Hz, 1H), 5.02 - 4.92 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.47 - 3.39 (m, 4H), 3.04 - 2.90 (m, 5H), 2.87 - 2.77 (m, 1H), 2.68 - 2.55 (m, 1H), 2.18 - 2.11 (m, 1H), 1.74 (s, 2H), 1.65 - 1.63 (m, 4H), 1.48 (s, 9H), 1.43 (s, 2H). LC-MS(ESI ⁺ )m/z 632.4(M+H) ⁺ .

Step 2 - 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 316 umol) in TFA (2 mL) was added TfOH (0.2 mL). The mixture was then stirred at 60° C. for 2 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 90% yield, TFA) as a brown solid. LC-MS (ESI ⁺ ) m/z 412.2 (M+H) ⁺ .

Step 3 - 9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (150 mg, 285 umol, TFA) in DCM (4 mL) was added TEA (79.4 uL, 570 umol) and Boc ₂ O (93.4 mg, 428 umol), then the mixture was stirred at 25 °C for 10 h. Upon completion, the mixture was diluted with DCM (100 mL) and extracted with water (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give the title compound (140 mg, 96% yield) as a brown solid. ^1H NMR (400 MHz, _CDCl3 -d) δ 8.46 - 8.34 (m, 1H), 7.02 - 6.92 (m, 2H), 6.57 (d, J = 7.2 Hz, 1H), 5.22 (dd, J = 5.2, 12.4 Hz, 1H), 3.99 - 3.90 (m, 1H), 3.77 (s, 3H), 3.46 - 3.40 (m, 4H), 2.97 - 2.88 (m, 5H), 2.83 (dd, J = 4.8, 13.2 Hz, 1H), 2.77 - 2.73 (m, J = 4.0, 15.2 Hz, 1H), 2.22 - 2.16 (m, J = 2.8, 5.2, 10.8 Hz, 1H), 1.74 (s, 3H), 1.65 - 1.63 (m, J = 8.0 Hz, 4H), 1.48 (s, 9H). LC-MS(ESI ⁺ )m/z 512.4(M+H) ⁺ .

Step 4 - 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 97.7 umol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the title compound (40.0 mg, 99% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 412.1 (M+H) ⁺ .

4-Benzylsulfanyl-2-methyl-aniline (Intermediate DE)

Step 1 - 4-benzylsulfanyl-2-methyl-1-nitrobenzene

A mixture of 4-fluoro-2-methyl-1-nitro-benzene (20.0 g, 128 mmol, CAS#446-33-3), BnSH (18.1 mL, 154 mmol), and DIEA (33.3 g, 257 mmol, 44.9 mL) in DMF (200 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 80 °C under _N2 atmosphere for 16 h. Upon completion, the reaction mixture was quenched with NaClO (10 mL) at 25 °C, then diluted with _H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuum to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (26.0 g, 76% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J=4.0 Hz, 1 H) 7.51 - 7.37 (m, 5 H) 7.30 - 7.25 (m, 2 H) 4.34 (s, 2 H) 2.69 (s, 3 H). LC-MS(ESI ⁺ )m/z 260.0(M+H) ⁺ .

Step 2 - 4-benzylsulfanyl-2-methyl-aniline

A mixture of 4-benzylsulfanyl-2-methyl-1-nitro-benzene (18.0 g, 69.4 mmol), Fe (23.2 g, 416 mmol), NH ₄ Cl (37.1 g, 694 mmol) in EtOH (180 mL) and H ₂ O (36 mL) was degassed and purged with N ₂ three times, then the mixture was stirred at 80 °C under N ₂ atmosphere for 1.5 h. Upon completion, the reaction mixture was diluted with H ₂ O 100 mL and extracted with EA (60 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 10/1) to give the title compound (63 g, yield 98%) as a black oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.29 - 7.18 (m, 5H) 6.99 (s, 1H) 6.93 (d, J = 1.6 Hz, 1H) 6.57 (d, J = 8.0 Hz, 1H) 4.99 (s, 2H) 3.96 (s, 2H) 2.03 (s, 3H).

5-Bromo-2-chloro-N-isopropyl-pyrimidin-4-amine (Intermediate DF)

To a solution of 5-bromo-2,4-dichloro-pyrimidine (10.0 g, 43.8 mmol, 5.62 mL, CAS#36082-50-5) in ACN (250 mL) was added TEA (5.77 g, 57.0 mmol, 7.94 mL) and propan-2-amine (3.37 g, 57.0 mmol, 4.90 mL) at 0 °C for 30 min. The mixture was then stirred at 25 °C for 15.5 h. Upon completion, the reaction mixture was diluted with H ₂ O (200 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (10 g, 90% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 251.8 (M+H) ⁺ .

4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate DG)

Step 1 - N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-isopropyl-pyrimidine-2,4-diamine

To a solution of 4-benzylsulfanyl-2-methyl-aniline (1.00 g, 4.36 mmol, intermediate DE) in IPA (10 mL) was added 5-bromo-2-chloro-N-isopropyl-pyrimidin-4-amine (1.20 g, 4.80 mmol, intermediate DF) and TFA (9.94 g, 87.2 mmol, 6.46 mL) at 20 °C under nitrogen flow. The reaction was then stirred at 80 °C under nitrogen atmosphere for 20 h. Upon completion, the mixture was diluted with H ₂ O (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with NaHCO ₃ (30 mL), then with brine (30 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in reduced pressure. The mixture was purified by pre-HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 20 min) to give the title compound (600 mg, 31% yield) as a black solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.25 (s, 1H), 7.91 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.36 - 7.25 (m, 4H), 7.23 (d, J = 6.8 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 4.17 (s, 3H), 2.16 (s, 3H), 1.15 (d, J = 6.4 Hz, 6H). LC-MS(ESI ⁺ )m/z 444.9(M+H) ⁺ .

Step 2 - (E)-3-[2-(4-benzylsulfanyl-2-methyl-anilino)-4-(isopropylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester

To a mixture of N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-isopropyl-pyrimidine-2,4-diamine (2.20 g, 4.96 mmol), TEA (1.51 g, 14.8 mmol, 2.07 mL), and Pd(PPh ₃ ) ₄ (1.15 g, 992 umol) in DMF (25 mL) was added methyl prop-2-enoate (3.11 g, 36.1 mmol, 3.25 mL). The mixture was degassed and purged with N ₂ three times, then the mixture was stirred at 90 °C under N ₂ atmosphere for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 °C, then extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 5/1) (Rf=0.5, PE:EA=2:1) to give the title compound (1.3 g, yield 58%) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.50 (s, 1H), 8.31 (s, 1H), 7.78 (d, J = 15.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.37 - 7.08 (m, 9H), 6.31 (d, J = 15.2 Hz, 1H), 4.18 (s, 2H), 3.68 (s, 3H), 2.18 (s, 3H), 1.16 - 1.10 (m, 6H). LC-MS(ESI ⁺ )m/z 449.5(M+H) ⁺ .

Step 3 - 2-(4-benzylsulfanyl-2-methyl-anilino)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of (E)-methyl 3-[2-(4-benzylsulfanyl-2-methyl-anilino)-4-(isopropylamino)pyrimidin-5-yl]prop-2-enoate (110 mg, 245 umol) in DMF (2 mL) was added t-BuOK (82.5 mg, 735 umol). The mixture was stirred at 25° C. for 30 min. The mixture was then heated to 120° C. and stirred for 1 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , PE:EA=1:1) (Rf=0.5, PE:EA=1:1) to give the title compound (50 mg, 48% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.27 (s, 1H), 8.64 (s, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.38 - 7.16 (m, 8H), 6.25 (d, J = 9.2 Hz, 1H), 5.61 - 5.42 (m, 1H), 4.22 (s, 2H), 2.17 (s, 3H), 1.34 (d, J = 5.2 Hz, 6H). LC-MS(ESI ⁺ ) m/z 867.3(M+H) ⁺ .

Step 4 - 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 240 umol) in ACN (1 mL), AcOH (0.1 mL), H ₂ O (0.01 mL) was added NCS (128 mg, 960 umol). The mixture was stirred at 25 °C in the dark for 16 h. Upon completion, the mixture was quenched with H ₂ O (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in reduced pressure. The residue was purified by prep-TLC (SiO ₂ , PE:EA=1:1) (Rf=0.56, PE:EA=1:1) to give the title compound (35 mg, 34% yield) as a yellow solid: LC-MS (ESI ⁺ ) m/z 426.8 (M+H) ⁺ .

3-[3-Methyl-2-oxo-5-(4-oxo-1-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (Intermediate DH)

Step 1 - 3-[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (635 mg, 4.44 mmol, CAS#177-11-7) in toluene (10 mL) was added LiHMDS (1 M, 17.7 mL) and the mixture was then stirred at 110° C. for 30 minutes. Next, 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol, intermediate DA), RuPhos Pd G3 (494 mg, 591 umol), and RuPhos (275 mg, 591 umol) were added and the mixture was stirred at 110° C. for 1.5 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (500 mg, 42% yield) as a grey solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 6.96 - 6.82 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 3.91 (s, 4H), 3.23 - 3.14 (m, 5H), 2.95 - 2.83 (m, 2H), 2.73 - 2.58 (m, 3H), 2.07 (s, 1H), 2.03 - 1.94 (m, 1H), 1.78 - 1.70 (m, 4H). LC-MS(ESI ⁺ )m/z 401.0(M+H) ⁺ .

Step 2 - 3-[3-methyl-2-oxo-5-(4-oxo-1-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione

A mixture of 3-[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg, 249 umol) in HCOOH (12.0 mg) was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (80 mg, 80% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 537.1 (M+H) ⁺ .

4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide (Intermediate DI)

Step 1 - 4-[3-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (68.3 mg, 280 umol, CAS# 373608-48-1) in DMF (1 mL) was added DIEA (90.7 mg, 702 umol) followed by 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (100 mg, 234 umol, Intermediate DG). The mixture was stirred at 25° C. for 10 minutes. Upon completion, the reaction mixture was concentrated in vacuo to provide the title compound (100 mg, 67% yield) as a grey oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.65 (s, 1H), 8.81 - 8.63 (m, 1H), 8.25 - 8.08 (m, 1H), 7.85 - 7.71 (m, 3H), 7.69 - 7.57 (m, 2H), 7.53 - 7.37 (m, 2H), 2.37 - 2.33 (m, 3H), 2.07 (d, J = 2.0 Hz, 1H), 1.77 - 1.64 (m, 2H), 1.39 (d, J = 1.6 Hz, 9H), 1.27 (s, 6H), LC-MS(ESI ⁺ ) m/z 633.9(M+H) ⁺ .

Step 2 - 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide

To a solution of tert-butyl 4-[3-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylate (50 mg, 78.8 umol) in DCM (1 mL) was added TFA (770 mg) and the mixture was then stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (50 mg, 97% yield) as a pale yellow oil. LC-MS (ESI ⁺ ) m/z 534.1 (M+H) ⁺ .

tert-Butyl 4-but-3-enylpiperazine-1-carboxylate (Intermediate DJ)

To a solution of 4-bromobut-1-ene (2.83 g, 20.9 mmol, CAS#5162-44-7) and tert-butyl piperazine-1-carboxylate hydrochloride (3.00 g, 13.4 mmol, CAS#57260-71-6) in THF (100 mL) was added K ₂ CO ₃ (6.69 g, 48.4 mmol) and TBAI (300 mg, 812 umol). The mixture was then stirred at 70 °C for 15 h. Upon completion, the mixture was filtered, diluted with water (100 mL) and extracted with EA (30 mL x 3). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=15:1 to 1:1) to give the title compound (1.50 g, 46% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.86 - 5.76 (m, 1H), 5.09 - 5.00 (m, 2H), 3.48 - 3.40 (m, 4H), 2.45 - 2.39 (m, 6H), 2.28 - 2.23 (m, 2H), 1.47 (s, 9H). LC-MS(ESI ⁺ )m/z 241.1(M+H) ⁺ .

4-(1,3-dioxolan-2-yl)piperidine (Intermediate DL)

Step 1 - Benzyl 4-(1,3-dioxolan-2-yl)piperidine-1-carboxylate

A solution of benzyl 4-formylpiperidine-1-carboxylate (20.0 g, 80.9 mmol, CAS#138163-08-3), PTSA (1.4 g, 8.09 umol) and ethylene glycol (5.52 g, 88.9 mmol, CAS#107-21-1) in toluene (200 mL) was refluxed at 130° C. for 16 h. Upon completion, the reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (15.0 g, 63% yield). ^1H NMR (400 MHz, _CDCl3 ) δ 7.43 - 7.28 (m, 5H), 5.13 (s, 2H), 4.65 (d, J = 4.4 Hz, 1H), 4.24 (s, 2H), 3.99 - 3.82 (m, 4H), 2.77 (s, 2H), 1.85 - 1.64 (m, 3H), 1.42 - 1.26 (m, 2H).

Step 2 - 4-(1,3-dioxolan-2-yl)piperidine

To a solution of benzyl 4-(1,3-dioxolan-2-yl)piperidine-1-carboxylate (5 g, 20 mmol) in MeOH (100 mL) was added Pd/C (1.5 g, 1.4 mmol, 10 wt%) under _N2 . The suspension was degassed in vacuum and purged with _H2 several times. The mixture was stirred at 25° C. under _H2 (15 PSI) for 4 h. Upon completion, the reaction mixture was filtered and concentrated in vacuum to give the title compound (2.3 g, 85% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 4.62 (d, J = 4.8 Hz, 1H), 3.98 - 3.81 (m, 4H), 3.11 (d, J = 12.0 Hz, 2H), 2.60 (m, 2H), 1.98 (s, 1H), 1.73 (d, J = 14.4 Hz, 2H), 1.69 - 1.62 (m, 1H), 1.38 - 1.24 (m, 2H).

1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (Intermediate DM)

Step 1 - 3-[5-[4-(1,3-dioxolan-2-yl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 4-(1,3-dioxolan-2-yl)piperidine (500 mg, 3.18 mmol, intermediate DL) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.08 g, 3.18 mmol, intermediate DA) in toluene (15 mL) was added RuPhos (148 mg, 318 umol), RuPhos Pd G ₃ (266 mg, 318 umol) and LiHMDS (1M, 19.0 mL). Upon completion, the reaction mixture was acidified to pH=7 with HCOOH and concentrated in vacuo. The residue was triturated with PE/EA (3/1), filtered and the filter cake was triturated with water. The solid was filtered and dried in vacuo to give the title compound (1.1 g, 83% yield) as a grey solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.05 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 2.0, 8.4 Hz, 1H), 5.28 (dd, J = 5.2, 12.8 Hz, 1H), 4.61 (d, J = 5.2 Hz, 1H), 3.93 - 3.75 (m, 4H), 3.62 (d, J = 12.4 Hz, 2H), 3.37 - 3.30 (m, 3H), 2.95 - 2.82 (m, 1H), 2.67 (dd, J = 4.4, 12.8 Hz, 1H), 2.63 - 2.55 (m, 3H), 2.02 - 1.93 (m, 1H), 1.78 - 1.72 (m, 2H), 1.65 - 1.56 (m, 1H), 1.50 - 1.39 (m, 2H).

Step 2 - 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde

A solution of 3-[5-[4-(1,3-dioxolan-2-yl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg, 241 umol) in HCOOH (3 mL) was stirred at 50° C. for 3 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (89 mg, 99% yield) as a brown oil. LCMS (ESI ⁺ ) m/z 371.0 (M+H) ⁺ .

8-Isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate DN)

Step 1 - 5-bromo-N-isopropyl-2-methylsulfanyl-pyrimidin-4-amine

To a solution of 5-bromo-2-chloro-N-isopropyl-pyrimidin-4-amine (10.0 g, 39.9 mmol, intermediate DF) in DMF (110 mL) was added NaSMe (7.12 g, 101 mmol, 6.47 mL). The mixture was stirred at 25 °C under _N2 for 16 h. Upon completion, the reaction mixture was quenched with _H2O (100 mL) at 25 °C and then extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over _{anhydrous Na2SO4} , filtered and concentrated in reduced pressure to give the title compound (9.50 g, 90% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.12 (s, 1H), 7.95 (s, 1H), 4.32 - 4.25 (m, 1H), 2.89 (s, 3H), 2.73 (s, 3H), 2.41 (s, 3H). LC-MS (ESI ⁺ ) m/z 263.8 (M+H) ⁺ .

Step 2 - (E)-3-[4-(isopropylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoic acid methyl ester

A mixture of 5-bromo-N-isopropyl-2-methylsulfanyl-pyrimidin-4-amine (9.50 g, 36.2 mmol), methyl prop-2-enoate (22.3 g, 259 mmol, 23.3 mL, CAS#96-33-3), Pd(PPh ₃ ) ₄ (4.19 g, 3.62 mmol), and TEA (11.0 g, 108 mmol, 15.0 mL) in DMF (100 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 90 °C under N ₂ atmosphere for 32 h. Upon completion, the reaction mixture was quenched with H ₂ O (100 mL) at 25 °C and then extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1-3/1) (Rf=0.40, PE:EA=1:1) to give the title compound (5.80 g, 59% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 - 8.30 (m, 1H), 7.79 (d, J = 15.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 6.55 - 6.43 (m, 1H), 4.35 (d, J = 6.8, 13.4 Hz, 1H), 3.71 (s, 3H), 2.44 (s, 3H), 1.19 (d, J = 6.4 Hz, 6H). LC-MS(ESI ⁺ )m/z 268.1(M+H) ⁺ .

Step 3 - 8-Isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

A mixture of (E)-methyl 3-[4-(isopropylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop- ₂ -enoate (5.73 g, 21.4 mmol), DBU (16.3 g, 107 mmol, 16.1 mL) in NMP (50.0 mL) was degassed and purged with N 3 times. The mixture was then stirred at 120 °C under N ₃ atmosphere for 1 h. Upon completion, the mixture was diluted with H ₂ O (300 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), then dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum. The mixture was purified by reverse phase (0.1% FA) to give the title compound (4.20 g, 83% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.84 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 5.75 - 5.56 (m, 1H), 2.59 (s, 3H), 1.53 (d, J = 6.8 Hz, 6H). LC-MS(ESI ⁺ )m/z 236.1(M+H) ⁺ .

4-[[6-(difluoromethyl)-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate DO)

Step 1 - 6-[chloro(difluoro)methyl]-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a 15 mL vial equipped with a stir bar was added 4-phenylpyridine N-oxide (3.64 g, 21.0 mmol), 8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 8.50 mmol, intermediate DN), and Ru(bpy) _3Cl2.6H2O ( _63.6 mg, 85.0 umol) in dry ACN (20 mL), followed by 2-chloro-2,2-difluoro-acetic acid ( ₂ -chloro-2,2-difluoro-acetyl) (5.16 g, 21.0 mmol, CAS# 2834-28-3). The vial was sealed and placed under nitrogen and added. The reaction was stirred and irradiated with a 34 W blue LED lamp (2 cm away) for 16 hours, using cooling water to maintain the reaction temperature at 25°C. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 10/1) (Rf=0.55, PE:EA=1:1) to give the title compound (1.37 g, 50% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 8.50 (s, 1H), 5.82 - 5.64 (m, 1H), 2.63 (s, 3H), 1.57 (d, J = 6.8 Hz, 6H). LC-MS(ESI ⁺ )m/z 319.6(M+H) ⁺ .

Step 2 - 6-(difluoromethyl)-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

A mixture of 6-[chloro(difluoro)methyl]-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (200 mg, 625 umol), Pd/C (10.0 mg, 6.25 umol, 10 wt%), Na ₂ CO ₃ (99.0 mg, 938 umol) in THF ( ₂ mL) was degassed and purged with H 2 three times. The mixture was then stirred at 25° C. under H ₂ atmosphere for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1 to 10/1) (Rf=0.70, PE:EA=3:1) to give the title compound (70.0 mg, 39% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.00 (s, 1H), 8.28 (s, 1H), 5.87 - 5.59 (m, 1H), 3.36 - 3.26 (m, 1H), 2.62 (s, 3H), 1.56 (d, J = 6.8 Hz, 6H). LC-MS(ESI ⁺ )m/z 286.0(M+H) ⁺ .

Step 3 - 6-(difluoromethyl)-8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-(difluoromethyl)-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (260 mg, 911 umol) in DCM (2 mL) was added m-CPBA (740 mg, 3.65 mmol, 85% solution). The mixture was stirred at 40° C. for 3 h. Upon completion, the mixture was quenched with NaHCO ₃ (10 mL) and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1 to 10/1) to give the title compound (100 mg, 34% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 317.9 (M+H) ⁺ .

Step 4 - 2-(4-benzylsulfanyl-2-methyl-anilino)-6-(difluoromethyl)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one

A mixture of 6-(difluoromethyl)-8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (70.0 mg, 220 umol), 4-benzylsulfanyl-2-methyl-aniline (151 mg, 661 umol, intermediate DE), TFA (251 mg, 2.21 mmol, 163 uL) in IPA (2 mL) was then stirred at 90° C. for 5 hours. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (27.0 mg, 26% yield) as a brown oily liquid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.56 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 7.37 - 7.17 (m, 8H), 6.88 (t, J = 56.0 Hz, 1H), 5.59 - 5.37 (m, 1H), 4.23 (s, 2H), 2.17 (s, 3H), 1.34 (s, 6H). LC-MS(ESI ⁺ )m/z 467.2(M+H) ⁺ .

Step 5 - 4-[[6-(difluoromethyl)-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-6-(difluoromethyl)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one (22.0 mg, 47.1 umol) in ACN (1 mL), AcOH (0.1 mL), and H ₂ O (0.01 mL) was added NCS (16.0 mg, 126 umol). The mixture was stirred at 25 °C in the dark for 1 h. Upon completion, the mixture was diluted with H ₂ O (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in reduced pressure to give the title compound (20.0 mg, 95% yield) as a brown oily liquid. LC-MS (ESI ⁺ ) m/z 442.9 (M+H) ⁺ .

tert-Butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate (Intermediate DP)

Step 1 - 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl acetate

To a solution of 4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexanol (8.60 g, 23.3 mmol, intermediate CT) and Rh ₂ (OAc) ₄ (1.03 g, 2.33 mmol) in DCM (40 mL) was added a solution of 2-ethyl diazoacetate (10.6 g, 93.3 mmol) in DCM (40 mL). The mixture was degassed and purged with N ₂ three times, and the mixture was stirred at 25 °C under N ₂ atmosphere for 12 h. Upon completion, the mixture was diluted with DCM (80 mL) and the organic layer was washed with H ₂ O (2 × 80 mL), brine (2 × 80 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum. The mixture was purified by silica gel column (PE:EA = 10:1) to give the title compound (10.0 g, 94% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.72 - 7.61 (m, 4H), 7.48 - 7.32 (m, 6H), 4.28 - 4.25 (m, 2H), 4.12 (s, 2H), 3.46 (d, J = 6.0 Hz, 2H), 3.32 - 3.22 (m, 1H), 2.15 - 2.04 (m, 2H), 1.91 - 1.81 (m, 2H), 1.54 - 1.45 (m, 1H), 1.32 - 1.28 (m, 5H), 1.09 - 0.99 (m, 2H), 1.05 (s, 9H).

Step 2 - 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethanol

To a solution of LAH (626 mg, 16.5 mmol) in THF (25 mL) was added dropwise a solution of 2-[4-[[tertbutyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl acetate (5.00 g, 11.0 mmol) in THF (25 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Upon completion, the mixture was quenched with H ₂ O (0.62 mL) and then a solution of 15% NaOH (0.62 mL) was added dropwise. The mixture was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo to give the title compound (3.15 g, 69% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.76 - 7.61 (m, 4H), 7.49 - 7.33 (m, 6H), 3.81 - 3.66 (m, 3H), 3.63 - 3.57 (m, 2H), 3.50 - 3.45 (m, 2H), 3.28 - 3.18 (m, 1H), 2.15 - 2.04 (m, 2H), 1.88 - 1.83 (m, 2H), 1.61 - 1.46 (m, 1H), 1.28 - 1.20 (m, 2H), 1.10 - 0.96 (m, 2H), 1.05 (s, 9H).

Step 3 - 4-Methylbenzenesulfonate 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl

To a solution of 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethanol (3.15 g, 7.63 mmol) in DCM (40 mL) was added TEA (1.13 g, 11.1 mmol), DMAP (170 mg, 1.39 mmol) and TosCl (1.59 g, 8.35 mmol). The mixture was stirred at 25° C. for 16 h. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=10:1) to give the title compound (2.86 g, 90% yield) as a colorless oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.88 - 7.76 (m, 2H), 7.68 - 7.60 (m, 4H), 7.44 - 7.31 (m, 8H), 4.19 - 4.12 (m, 2H), 3.72 - 3.62 (m, 2H), 3.45 (d, J = 6.4 Hz, 2H), 3.19 - 3.06 (m, 1H), 2.45 (s, 3H), 2.00 - 1.90 (m, 2H), 1.88 - 1.75 (m, 2H), 1.52 - 1.42 (m, 1H), 1.20 - 1.10 (m, 2H), 1.05 (s, 9H), 1.01 - 0.92 (m, 2H).

Step 4 - 2-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]isoindoline-1,3-dione

To a solution of 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl 4-methylbenzenesulfonate (2.86 g, 5.05 mmol) in DMF (20 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (1.40 g, 7.57 mmol). The mixture was stirred at 50° C. for 5 h. Upon completion, the mixture was diluted with H ₂ O (150 mL) and extracted with EA (3×50 mL). The organic layer was washed with brine (3×40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (2.7 g, 98% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.89 - 7.83 (m, 2H), 7.74 - 7.69 (m, 2H), 7.68 - 7.61 (m, 4H), 7.45 - 7.34 (m, 6H), 3.95 - 3.82 (m, 2H), 3.77 - 3.68 (m, 2H), 3.44 (d, J = 6.1 Hz, 2H), 3.28 - 3.15 (m, 1H), 2.03 - 1.94 (m, 2H), 1.87 - 1.75 (m, 2H), 1.54 - 1.40 (m, 1H), 1.22 - 1.12 (m, 2H), 1.04 (s, 9H), 1.02 - 0.90 (m, 2H).

Step 5 - 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethanamine

To a solution of 2-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]isoindoline-1,3-dione (2.7 g, 4.98 mmol) in EtOH (20 mL) was added NH ₂ NH ₂ .H ₂ O (3.19 g, 54.1 mmol, 3.10 mL, 85% solution). The mixture was stirred at 50° C. for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with DCM (30 mL) and filtered, and the filtrate was concentrated in vacuo to give the title compound (2.02 g, 98% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.70 - 7.63 (m, 4H), 7.47 - 7.35 (m, 6H), 3.54 (t, J = 4.8 Hz, 2H), 3.47 (d, J = 6.0 Hz, 2H), 3.25 - 3.15 (m, 1H), 2.90 (t, J = 5.2 Hz, 2H), 2.33 - 2.19 (m, 2H), 2.13 - 2.00 (m, 2H), 1.88 - 1.78 (m, 2H), 1.56 - 1.45 (m, 1H), 1.28 - 1.20 (m, 2H), 1.06 (s, 9H), 1.04 - 0.94 (m, 2H).

Step 6 - tert-Butyl N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]carbamate

To a solution of 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethanamine (2 g, 5 mmol) in DCM (20 mL) was added TEA (983 mg, 9.72 mmol, 1.35 mL) and (Boc) ₂ O (1.27 g, 5.83 mmol, 1.34 mL). The mixture was stirred at 25° C. for 3 h. Upon completion, the mixture was concentrated in vacuum. The mixture was purified by silica gel column (PE:EA=10:1) to give the title compound (1.88 g, 75% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 7.77 - 7.58 (m, 4H), 7.53 - 7.32 (m, 6H), 5.00 - 4.79 (m, 1H), 3.53 (t, J = 5.2 Hz, 2H), 3.47 (d, J = 6.0 Hz, 2H), 3.33 - 3.25 (m, 2H), 3.22 - 3.12 (m, 1H), 2.10 - 1.99 (m, 2H), 1.89 - 1.80 (m, 2H), 1.54 - 1.46 (m, 1H), 1.49 (s, 9H), 1.27 - 1.15 (m, 2H), 1.06 (s, 9H), 1.05 - 0.93 (m, 2H).

Step 7 - tert-butyl N-[2-[4-(hydroxymethyl)cyclohexoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]carbamate (1.78 g, 3.48 mmol) in THF (15 mL) was added TBAF (1.00 M, 5.22 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo and then the mixture was purified by silica gel column (PE:EA=1:1) to give the title compound (950 mg, yield 99%) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 5.00 - 4.75 (m, 1H), 3.53 (t, J = 5.2 Hz, 2H), 3.47 (d, J = 6.4 Hz, 2H), 3.34 - 3.26 (m, 2H), 3.25 - 3.13 (m, 1H), 2.13 - 2.03 (m, 2H), 1.90 - 1.80 (m, 2H), 1.56 - 1.50 (m, 1H), 1.46 (s, 9H), 1.30 - 1.16 (m, 3H), 1.05 - 0.91 (m, 2H).

Step 8 - tert-Butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate

To a solution of tert-butyl N-[2-[4-(hydroxymethyl)cyclohexoxy]ethyl]carbamate (800 mg, 2.93 mmol) in DCM (20 mL) was added DMP (1.49 g, 3.51 mmol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was diluted with DCM (100 mL) and quenched with saturated Na ₂ S ₂ O ₃ (50 mL) and washed with saturated NaHCO ₃ (3×50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (790 mg, 99% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 9.65 (d, J = 1.2 Hz, 1H), 5.05 - 4.67 (m, 1H), 3.57 - 3.49 (m, 2H), 3.37 - 3.17 (m, 3H), 2.17 - 1.99 (m, 4H), 1.46 (s, 10H), 1.41 - 1.23 (m, 4H).

3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate DQ)

Step 1 - tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclohexoxy]ethyl]carbamate

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (756 mg, 1.66 mmol, TFA, Intermediate DB), tert-butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate (500 mg, 1.84 mmol, Intermediate DP) in DMF (4 mL) and THF (16 mL) was added TEA (372 mg, 3.69 mmol). The mixture was stirred at -10°C for 0.5 h. HOAc (331 mg, 5.53 mmol, 316 uL) was then added and the mixture was stirred at -10°C for 0.5 h. NaBH(OAc) (781 mg, 3.69 mmol) _was then added and the mixture was stirred at -10°C for 1 h. Upon completion, the mixture was quenched with _H2O (0.5 mL) and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to afford the title compound (630 mg, 57% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.07 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.79 - 6.67 (m, 1H), 5.37 - 3.29 (m, 1H), 3.33 (s, 3H), 3.27 - 3.12 (m, 7H), 3.05 - 3.02 (m, 2H), 2.95 - 2.82 (m, 2H), 2.74 - 2.66 (m, 2H), 2.64 - 2.55 (m, 2H), 2.06 - 1.94 (m, 3H), 1.90 - 1.70 (m, 6H), 1.67 - 1.53 (m, 1H), 1.37 (s, 9H), 1.18 - 1.07 (m, 2H), 1.03 - 0.86 (m, 2H), LC-MS(ESI ⁺ ) m/z 598.3(M+H) ⁺ .

Step 2 - 3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclohexoxy]ethyl]carbamate (530 mg, 886 umol) in DCM (8 mL) was added TFA (2.04 g, 17.9 mmol, 1.32 mL). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (530 mg, 97% yield, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 498.2 (M+H) ⁺ .

tert-Butyl N-[4-(4-piperidyl)butyl]carbamate (Intermediate DR)

Step 1 - tert-Butyl N-[4-(4-pyridyl)butyl]carbamate

A mixture of tert-butyl N-(4-bromobutyl)carbamate (50.4 mg, 0.2 mmol, 41.0 uL, CAS# 164365-88-2) and 4-bromopyridine (24.3 mg, 153 umol, CAS# 1120-87-2) in ACN (1 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 25°C under _N2 atmosphere for 12 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250 x 50 mm x 10 um; mobile phase: [water (FA)-ACN]; B%: 35%-50%, 30 min) to give the title compound (400 mg, 26% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.49 (d, J = 4.4 Hz, 2H), 7.12 (d, J = 4.0 Hz, 2H), 4.53 (s, 1H), 3.15 (d, J = 6.4 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 1.72 - 1.62 (m, 2H), 1.57 - 1.50 (m, 2H), 1.44 (s, 9H). LC-MS(ESI ⁺ ) m/z 251.1(M+H) ⁺ .

Step 2 - tert-Butyl N-[4-(4-piperidyl)butyl]carbamate

To a solution of tert-butyl N-[4-(4-pyridyl)butyl]carbamate (400 mg, 1.60 mmol) in EtOH (5 mL) was added PtO ₂ (362 mg, 1.60 mmol) and HOAc (95.9 mg, 1.60 mmol, 92.0 uL) under N _2. The suspension was degassed under reduced pressure and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 12 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (500 mg, 98% yield, HOAc salt) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 4.56 (s, 1H), 3.38 (d, J = 12.4 Hz, 2H), 3.11 (d, J = 5.6 Hz, 2H), 2.82 (t, J = 11.6 Hz, 2H), 1.83 (d, J = 11.6 Hz, 2H), 1.44 (s, 15H), 1.32 (s, 4H). LC-MS (ESI ⁺ ) m/z 257.3(M+H) ⁺ .

1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (Intermediate DS)

To a solution of 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (2 g, 9 mmol, CAS#589-87-8) and 1-bromo-4-iodo-benzene (2.68 g, 9.49 mmol, CAS#504-07-4) in DMF (30 mL) was added DBU (2.89 g, 18.9 mmol) and CuI (1.81 g, 9.49 mmol). The mixture was stirred at 140° C. for 16 h. Upon completion, the reaction mixture was filtered and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give the title compound (2.5 g, 68% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 390.7 (M+H) ⁺ .

1-[4-[4-(4-aminobutyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate DT)

Step 1 - tert-butyl N-[4-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]butyl]carbamate

A mixture of tert-butyl N-[4-(4-piperidyl)butyl]carbamate (280 mg, 1.09 mmol, Intermediate DR), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (100 mg, 256 umol, Intermediate DS), Cs ₂ CO ₃ (502 mg, 1.54 mmol), and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide 3-chloropyridine; dichloropalladium (22.1 mg, 25.6 umol) in dioxane (1 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 38%-68%, 10 min) to give the title compound (200 mg, yield 66%) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.46 - 7.38 (m, 2H), 7.16 - 7.05 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.86 - 6.79 (m, 2H), 4.95 (s, 2H), 4.54 (s, 1H), 3.78 (s, 3H), 3.71 (t, J = 6.8 Hz, 2H), 3.64 (d, J = 12.4 Hz, 2H), 3.17 - 3.07 (m, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 11.6 Hz, 2H), 1.77 (d, J = 10.4 Hz, 2H), 1.53 - 1.47 (m, 2H), 1.45 (s, 9H), 1.40 - 1.26 (m, 7H). LC-MS(ESI ⁺ )m/z 565.3(M+H) ⁺ .

Step 2 - 1-[4-[4-(4-aminobutyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

A mixture of tert-butyl N-[4-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]butyl]carbamate (100 mg, 177 umol) and TfOH (26.5 mg, 177 umol, 15.6 uL) in TFA (1.2 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 70° C. under _N2 atmosphere for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give the title compound (61 mg, 76% yield, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 345.0 (M+H) ⁺ .

tert-Butyl N-[5-(4-piperidyl)pentyl]carbamate (Intermediate DU)

Step 1 - N-[5-(4-pyridyl)pentyl]carbamic acid tert-butyl

To a vial equipped with a stir bar was added 4-bromopyridine (1.00 g, 6.33 mmol, CAS# 1120-87-2), tert-butyl N-(5-bromopentyl)carbamate (2.19 g, 8.23 mmol, CAS# 83948-54-3), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (71.0 mg, 63.2 umol), NiCl ₂ .dtbbpy (37.7 mg, 94.9 umol), TTMSS (1.57 g, 6.33 mmol), and Na ₂ CO ₃ (1.34 g, 12.6 mmol) in DME (10 mL). The vial was sealed and placed under nitrogen and added. The reaction was stirred and irradiated with a 10 W blue LED lamp (3 cm away) for 14 h, using cooling water to maintain the reaction temperature at 25° C. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (Column: UniSil 10-120 C18 50×250 mm; Mobile phase: [Water (FA)-ACN]; B%: 1%-30%, 22 min) to give the title compound (800 mg, 48% yield) as a colorless solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.46 (d, J = 3.2 Hz, 2H) 7.08 (d, J = 4.4 Hz, 2H) 4.63 (s, 1H) 3.11 - 3.06 (m, 2H) 2.58 (t, J = 7.6 Hz, 2H) 1.67 - 1.59 (m, 2H) 1.51 - 1.46 (m, 2H) 1.42 (s, 9H) 1.37 - 1.30 (m, 2H). LC-MS(ESI ⁺ )m/z 264.9(M+H) ⁺ .

Step 2 - N-[5-(4-piperidyl)pentyl]carbamic acid tert-butyl

To a solution of tert-butyl N-[5-(4-pyridyl)pentyl]carbamate (800 mg, 3 mmol) in EtOH (8 mL) was added PtO ₂ (687 mg, 3.03 mmol) and AcOH (363 mg, 6.05 mmol) under N _2. The suspension was degassed under reduced pressure and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 12 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (775 mg, 95% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 4.61 (s, 1H) 3.35 (d, J = 12.4 Hz, 2H) 3.10 - 2.99 (m, 2H) 2.80 (t, J = 11.2 Hz, 2H) 1.79 (d, J = 11.6 Hz, 2H) 1.41 (s, 15H) 1.26 (s, 6H). LC-MS(ESI ⁺ )m/z 271.2(M+H) ⁺ .

1-[4-[4-(5-aminopentyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate DV)

Step 1 - N-[5-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]pentyl]carbamic acid tert-butyl

A mixture of tert-butyl N-[5-(4-piperidyl)pentyl]carbamate (34.7 mg, 128 umol, Intermediate DU), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (50.0 mg, 128 umol, Intermediate DS), _Cs2CO3 ( ₄₁₈ mg, 1.28 mmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (12.5 mg, 12.8 umol) and 4A molecular sieves (2.00 mg, 128 umol) in dioxane (1 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100° C. under _N2 atmosphere for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 43%-73%, 10 min) to give the title compound (50.0 mg, 67% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.05 - 8.04 (m, 1H) 7.43 (d, J = 8.4 Hz, 2H) 7.12 (d, J = 8.8 Hz, 2H) 6.93 (d, J = 8.8 Hz, 2H) 6.86 - 6.78 (m, 2H) 4.95 (s, 2H) 3.78 (s, 3H) 3.72 (t, J = 6.4 Hz, 2H) 3.64 (d, J = 12.4 Hz, 2H) 3.16 - 3.06 (m, 2H) 2.85 (t, J = 6.8 Hz, 2H) 2.68 (t, J = 11.6 Hz, 2H) 1.77 (d, J = 10.4 Hz, 2 H) 1.53 - 1.48 (m, 2 H) 1.45 (s, 9 H) 1.38 - 1.24 (m, 9 H). LC-MS(ESI ⁺ )m/z 579.3(M+H) ⁺ .

Step 2 - 1-[4-[4-(5-aminopentyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[5-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]pentyl]carbamate (50.0 mg, 86.3 umol) in TfOH (0.1 mL) was added TFA (924 mg, 8.10 mmol). The mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the title compound (30.0 mg, 97% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 359.1 (M+H) ⁺ .

N-Isopropylacetamidine (Intermediate DW)

To a solution of ethyl ethanimidate hydrochloride (10.0 g, 80.9 mmol, CAS# 2208-07-3) in IPA (60 mL) was added TEA (8.19 g, 80.9 mmol) and propan-2-amine (4.78 g, 80.9 mmol, CAS# 4432-77-3). The mixture was stirred at 25°C for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (5.5 g, 67% yield) as a colorless oil.

3-Chloro-4,4-diethoxy-butan-2-one (Intermediate DX)

To a stirred solution of diethoxymethoxyethane (16.0 g, 108 mmol, CAS#122-51-0) in DCM (150 mL) was added diethyloxonio(trifluoro)boranuide (32.6 g, 108 mmol, 47% solution) at −30° C. under N ₂ atmosphere. The reaction mixture was stirred at 25° C. for 1 h. Then 1-chloropropan-2-one (5.00 g, 54.0 mmol, CAS#78-95-5) was added quickly at −78° C. followed by DIPEA (20.9 g, 162 mmol). The reaction mixture was then stirred at −78° C. for 1 h. Saturated NaHCO ₃ (100 mL) was added to the reaction mass and stirred for 15 min and the layers were separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic layers were washed with _H2SO4 : _H2O (1:10) ratio, followed by water (2 x 100 mL), the organic layer was dried over _{anhydrous Na2SO4} and concentrated under reduced pressure to give the title compound (10.0 _g , 47% yield) as a red oil.

[4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl] trifluoromethanesulfonate (intermediate DY)

Step 1 - 1-(3-isopropyl-2-methyl-imidazol-4-yl)ethanone

A mixture of 3-chloro-4,4-diethoxy-butan-2-one (10.0 g, 51.3 mmol, intermediate DX), _N -isopropylacetamidine (5.15 g, 51.3 mmol, intermediate DW), _K2CO3 (21.3 g, 154 mmol) and 18-crown-6 (678 mg, 2.57 mmol) in ACN (100 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 80 °C under _N2 atmosphere for 16 h. The reaction mixture was partitioned between _H2O (100 mL) and EA (2 x 100 mL). The organic phase was separated, washed with brine (100 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM/IPA=100/1 to 10/1) to give the title compound (5.00 g, 58% yield) as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 5.43 - 5.22 (m, 1H), 2.54 (s, 3H), 2.46 (s, 3H), 1.52 (s, 3H), 1.50 (s, 3H). LCMS(ESI ⁺ )m/z 167.1(M+H) ⁺ .

Step 2 - (E)-3-(dimethylamino)-1-(3-isopropyl-2-methyl-imidazol-4-yl)prop-2-en-1-one

To a solution of 1-(3-isopropyl-2-methyl-imidazol-4-yl)ethanone (5.00 g, 30.0 mmol) in DMF (30 mL) was added DMF-DMA (3.94 g, 33.0 mmol, CAS#4637-24-5). The mixture was stirred at 130° C. for 16 h. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by column chromatography (SiO ₂ , DCM/IPA=100/1 to 10/1) to give the title compound (3.00 g, 45% yield) as a red solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.66 (d, J = 12.4 Hz, 1H), 7.48 (s, 1H), 5.49 (d, J = 12.4 Hz, 1H), 5.47 - 5.40 (m, 1H), 3.14 - 2.87 (m, 6H), 2.60 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H). LCMS (ESI ⁺ ) m/z 222.2 (M+H) ⁺ .

Step 3 - 4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-ol

A solution of (E)-3-(dimethylamino)-1-(3-isopropyl-2-methyl-imidazol-4-yl)prop-2-en-1-one (2.00 g, 9.04 mmol), CH ₃ ONa (1.95 g, 36.1 mmol) and urea (1.36 g, 22.5 mmol, CAS#506-89-8) in 1-butanol (20 mL) was stirred at 140° C. for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by prep-HPLC (column: Phenomenex C18 250×50 mm×10 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 0%-20%, 8 min) to give the title compound (1.10 g, 55% yield) as a white solid. LCMS (ESI ^<+> ) m/z 219.0 (M+H) ^<+> .

Step 4 - [4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl] = trifluoromethanesulfonate

To a solution of 4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-ol (550 mg, 2.52 mmol) in DCM (5 mL) was added TEA (509 mg, 5.04 mmol) and Tf ₂ O (746 mg, 2.65 mmol). The mixture was stirred at 0° C. for 1 h. Upon completion, the reaction mixture was partitioned between H ₂ O (50 mL) and DCM (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue affording the title compound (780 mg, 88% yield) as a red solid. LCMS (ESI ⁺ ) m/z 350.9 (M+H) ⁺ .

4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate DZ)

Step 1 - N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-amine

A mixture of [4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl] trifluoromethanesulfonate (780 mg, 2.23 mmol, Intermediate DY), 4-benzylsulfanyl-2-methyl- _aniline (459 mg, 2.00 mmol, Intermediate DE), Pd(OAc) (49.9 mg, 222 umol), BINAP (138 mg, 222 umol) and _CsCO ( _2.18 g, 6.68 mmol) in toluene (10 mL) was degassed and purged with _N three times. This mixture was then stirred at 100° C. under _N atmosphere for 16 h. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (270 mg, 28% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 430.4 (M+H) ⁺ .

Step 2 - 4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-amine (30.0 mg, 69.8 umol) in a mixture of ACN (1 mL), AcOH (0.1 mL) and H ₂ O (0.02 mL) was added NCS (23.3 mg, 174 umol). The mixture was stirred in the dark at 25° C. for 1 h. The mixture was diluted with water (15 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (28.0 mg, 98% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 405.7 (M+H) ⁺ .

N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate EA)

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.30 mmol, CAS#3932-97-6) in a mixed solvent of DCE (6 mL) and t-BuOH (6 mL) was added ZnCl ₂ (1 M, 2.77 mL) at 0° C. After 1 h, a solution of 4-benzylsulfanyl-2-methyl-aniline (528 mg, 2.30 mmol, intermediate DE) and TEA (256 mg, 2.5 mmol) in a mixed solvent of DCE (3 mL) and t-BuOH (3 mL) was added dropwise to the above solution. The mixture was then stirred at 25° C. for 16 h. Upon completion, the mixture was diluted with H ₂ O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with saturated NaCl (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=50:1-20:1) to give the title compound (600 mg, 63% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.66 - 8.60 (m, 1H), 7.40 - 7.35 (m, 2H), 7.31 - 7.28 (m, 2H), 7.28 - 7.21 (m, 3H), 7.20 - 7.16 (m, 1H), 4.24 (s, 2H), 2.15 (s, 3H). LC-MS(ESI ⁺ )m/z 410.0(M+H) ⁺ .

(1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate ED)

Step 1 - (1-(tert-butyl)-3-((1S,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate

To a mixture of (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzylcarbamate (1.00 g, 2.80 mmol, CAS#2460255-81-4) and 4-nitrophenyl carbonochloridate (845 mg, 4.20 mmol, CAS#7693-46-1) in DCM (10 mL) was added DMAP (34.1 mg, 279 umol) and pyridine (663 mg, 8.39 mmol) at 20 °C under _N2 atmosphere. The mixture was then stirred at 20 °C under nitrogen atmosphere for 10 h. Upon completion, the reaction mixture was poured into ice water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layer is washed with brine ( ₂₀ mL x 2) and then dried over _Na2SO4 . The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (1.4 g, yield 96%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.28 (d, J = 9.2 Hz, 2H), 7.48 - 7.31 (m, 6H), 6.31 - 6.05 (m, 2H), 5.30 - 5.23 (m, 1H), 5.21 (s, 2H), 3.23 - 3.09 (m, 1H), 2.62 (ddd, J = 7.2, 8.0, 14.8 Hz, 1H), 2.18 - 2.08 (m, 1H), 2.05 - 1.95 (m, 3H), 1.94 - 1.87 (m, 1H), 1.59 (s, 10H).

Step 2 - (1-(tert-butyl)-3-((1R,3S)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate

To a solution of [(1S,3R)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl](4-nitrophenyl)carbonate (600 mg, 1.15 mmol) and propan-2-amine (135 mg, 2.30 mmol) in THF (6 mL) was added DIEA (742 mg, 5.74 mmol). The mixture was stirred at 20° C. for 4 h. Upon completion, the reaction mixture was poured into ice water (6 mL) and extracted with DCM (6 mL×2). The combined organic phase was washed with brine (6 mL×2) and dried over Na ₂ SO _4. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (350 mg, 69% yield) as a colorless oil. LC-MS (ESI+) m/z 443.4 (M+H)+.

Step 3 - (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

To a solution of N-[2-tert-butyl-5-[(1R,3S)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]carbamate benzyl (350 mg, 790 umol) in EtOH (20 mL) was added Pd/C (400 mg, 377 umol, 10 wt%). The mixture was stirred at 20° C. under H ₂ atmosphere (15 psi) for 12 h. Upon completion, the reaction mixture was filtered and the filter cake was washed with EtOH (10 mL). The mixture was filtered and the filtrate was concentrated to give the title compound (260 mg) as a yellow oil. LC-MS (ESI+) m/z 309.2 (M+H)+.

4-((5-amino-1-(3-methylthiophene-2-carbonyl)-1H-1,2,4-triazol-3-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Intermediate EE)

Step 1 - tert-Butyl N-[4-(tert-butoxycarbonylamino)phenyl]sulfonylcarbamate

A solution of 4-aminobenzenesulfonamide (50 g, 290 mmol, 50 mL), (Boc) ₂ O (126 g, 580 mmol, 133 mL), DMAP (3.55 g, 29.0 mmol), and Et ₃ N (88.1 g, 871 mmol, 121 mL) in THF (200 mL) was stirred at 20° C. for 8 h. Upon completion, the reaction mixture was quenched by addition of H ₂ O (300 mL) at 20° C. and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane:methanol=1/0-50/1) to give the title compound (20 g, 19% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.99 - 7.88 (m, 2H), 7.57 - 7.46 (m, 2H), 3.50 (s, 1H), 1.53 (s, 9H), 1.41 - 1.38 (m, 9H).

Step 2 - (4-((tert-butoxycarbonyl)amino)phenyl)sulfonyl(2-(prop-2-yn-1-yloxy)ethyl)carbamate tert-butyl

To a solution of tert-butyl N-[4-(tert-butoxycarbonylamino)phenyl]sulfonylcarbamate (10 g, 26.8 mmol), 2-prop-2-ynoxyethanol (3.49 g, 34.9 mmol, CAS#3973-18-0) and PPh ₃ (9.16 g, 34.91 mmol) in toluene (150 mL) was slowly added dropwise a solution of DIAD (7.06 g, 34.9 mmol, 6.79 mL) in toluene (50 mL) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (200 mL) and extracted with ethyl acetate (150 mL×2). The combined organic layers are washed with brine (100 mL×2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (17 g) as a yellow oil. LC-MS (ESI ⁺ ) m/z 448.1 (M−H) ⁻ .

Step 3 - (4-((tert-butoxycarbonyl)amino)phenyl)sulfonyl(2-(prop-2-yn-1-yloxy)ethyl)carbamate tert-butyl

To a solution of tert-butyl N-[4-(tert-butoxycarbonylamino)phenyl]sulfonyl-N-(2-prop-2-ynoxyethyl)carbamate (17 g, 37.4 mmol) in DCM (300 mL) was added TFA (52.3 g, 459 mmol) at 20° C. under a stream of nitrogen. The reaction was then stirred at 20° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was concentrated to give a residue. The crude product was purified by reverse phase HPLC (0.1% NH3.H2O condition) to give the title compound (7 g, 74% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.63 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 6.40 (br s, 3H), 4.11 - 3.99 (m, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.19 - 3.09 (m, 2H), 2.43 (t, J = 2.4 Hz, 1H).

Step 4 - N-(2-(prop-2-yn-1-yloxy)ethyl)-4-thiocyanatobenzenesulfonamide

To a solution of thiocarbonyl dichloride (3.16 g, 27.5 mmol) in DCM (70 mL) was slowly added dropwise a solution of 4-amino-N-(2-prop-2-ynoxyethyl)benzenesulfonamide (7 g, 27.53 mmol) in DCM (70 mL) at 0 °C. The reaction was then stirred at 20 °C under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into water (150 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (3 mL x 2) and dried over sodium sulfate. The mixture was then filtered and the filtrate and concentrated to give the title compound (7 g, 86% yield) as a brown solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.86 (br d, J = 7.8 Hz, 2H), 7.32 (br d, J = 8.4 Hz, 2H), 5.31 - 5.16 (m, 1H), 4.08 (s, 2H), 3.56 (br t, J = 4.8 Hz, 2H), 3.18 (br d, J = 4.8 Hz, 2H), 2.49 - 2.41 (m, 1H).

Step 5 - 3,5-Dimethyl-N-((4-(N-(2-(prop-2-yn-1-yloxy)ethyl)sulfamoyl)phenyl)carbamothioyl)-1H-pyrazole-1-carboximidamide

To a solution of 3,5-dimethylpyrazole-1-carboxamidine; nitric acid (9.50 g, 47.2 mmol, CAS#22906-75-8) in DMF (140 mL) was added KOH (2.65 g, 47.24 mmol) at 0° C. under nitrogen flow. To this was slowly added a solution of 3,5-dimethyl-1H-pyrazole-1-carboximidamide (7 g, 23.62 mmol) in DMF (70 mL) dropwise at 0° C. The reaction was then stirred at 60° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (200 mL×2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 100:1 to 100:7) to give the title compound (2.7 g, 26% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.02 (s, 4H), 7.82 (d, J = 8.4 Hz, 2H), 5.96 (d, J = 10.0 Hz, 2H), 4.09 (d, J = 2.4 Hz, 2H), 3.57 (t, J = 5.2 Hz, 2H), 3.17 (t, J = 5.2 Hz, 2H), 2.44 (t, J = 2.4 Hz, 1H), 2.23 (d, J = 6.4 Hz, 6H).

Step 6 - 4-((5-amino-1H-1,2,4-triazol-3-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide

To a solution of 3,5-dimethyl-N-((4-(N-(2-(prop-2-yn-1-yloxy)ethyl)sulfamoyl)phenyl)carbamothioyl)-1H-pyrazole-1-carboximidamide (1 g, 2.30 mmol) in THF (20 mL) was added hydrazine; hydrate (1.29 g, 25.7 mmol) at 20° C. under nitrogen flow. The reaction was then stirred at 55° C. under nitrogen atmosphere for 3 hours. Upon completion, the reaction was concentrated to give a residue. The solid was refluxed in a solvent of EtOAc:PE=1:3 (50 mL) for 5 minutes. The mixture was then filtered and the filter cake was washed with EtOAc:PE=1:3 (30 mL) and dried in vacuum to give the title compound (320 mg, 41.34% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.29 (br s, 1H), 9.15 - 8.84 (m, 1H), 7.71 - 7.47 (m, 4H), 5.98 (s, 2H), 5.60 (br s, 1H), 4.07 (d, J = 2.4 Hz, 2H), 3.43 - 3.38 (m, 2H), 2.90 - 2.79 (m, 2H), 1.74 (s, 1H).

Step 7 - 4-((5-amino-1-(3-methylthiophene-2-carbonyl)-1H-1,2,4-triazol-3-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide

To a solution of 4-((5-amino-1H-1,2,4-triazol-3-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (280 mg, 832 umol) in pyridine (3 mL) and THF (3 mL) was added 3-methylthiophene-2-carbonyl chloride (267 mg, 1.66 mmol, CAS# 61341-26-2) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (15 mL×2). The combined organic layers are washed with brine (2×20 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to provide a residue. The residue was purified by prep-HPLC column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min) to give the title compound (120 mg, 31% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.92 (s, 1H), 8.05 (d, J = 5.2 Hz, 1H), 7.91 - 7.78 (m, 4H), 7.77 - 7.70 (m, 2H), 7.48 (t, J = 6.4 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 4.08 (d, J = 2.4 Hz, 2H), 3.44 - 3.40 (m, 2H), 2.89 (q, J = 6.0 Hz, 2H), 2.63 (s, 3H), 2.57 - 2.55 (m, 1H).

4-[(8-Cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate EF)

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-8-cyclopentyl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.26 mmol, synthesized by steps 1-2 of intermediate CW) in ACN (10 mL), AcOH (1 mL), H ₂ O (0.5 mL) was added NCS (754 mg, 5.65 mmol) in the dark. The mixture was stirred at 25° C. in the dark for 0.5 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA=0:1, P1, Rf=0.45) to give the title compound (900 mg, 95% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.81 (s, 1H), 8.82 (s, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.60 (s, 1H), 7.54 - 7.51 (m, 1H), 7.47 - 7.44 (m, 1H), 7.41 - 7.35 (m, 1H), 7.32 - 7.29 (m, 1H), 6.43 (d, J = 9.6 Hz, 1H), 5.77 - 5.63 (m, 1H), 2.31 (s, 3H), 2.16 (d, J = 4.8 Hz, 2H), 1.72 (s, 3H), 1.49 (s, 1H). LC-MS(ESI ⁺ )m/z 419.0(M+H) ⁺ .

3-[3-Methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate EG)

Step 1 - 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-2-nitro-benzoic acid methyl ester

To a solution of methyl 3-fluoro-2-nitro-benzoate (10.0 g, 50.2 mmol, CAS# 1214353-57-7), tert-butyl N-methyl-N-(4-piperidyl)carbamate (13.9 g, 65.2 mmol, CAS# 108612-54-0) in ACN (250 mL) was added DIEA (19.4 g, 150 mmol). The mixture was stirred at 50° C. for 16 h. Upon completion, the mixture was concentrated in vacuo. The mixture was triturated with H ₂ O (200 mL), filtered, and the filtrate was dried in vacuo to give the title compound (19.6 g, 99% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 7.85 (dd, J = 1.2, 8.0 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.73 - 7.66 (m, 1H), 3.84 (s, 3H), 4.04 - 3.68 (m, 1H), 3.11 - 3.01 (m, 2H), 2.95 - 2.82 (m, 2H), 2.70 (s, 3H), 1.79 - 1.55 (m, 4H), 1.41 (s, 9H), LC-MS(ESI ⁺ ) m/z 416.1(M+Na) ⁺ .

Step 2 - 2-amino-3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]benzoic acid methyl ester

To a solution of methyl 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-2-nitro-benzoate (18.6 g, 47.2 mmol) in THF (190 mL) was added Pd/C (2.00 g, 10% wt). The mixture was stirred at 25° C. under H ₂ (15 Psi) for 16 h. Upon completion, the mixture was filtered and concentrated in vacuo to afford the title compound (17.1 g, 99% yield) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ 7.61 - 7.51 (m, 1H), 7.10 - 7.01 (m, 1H), 6.52 (t, J = 8.0 Hz, 1H), 6.25 - 6.04 (m, 2H), 4.20 - 3.88 (m, 1H), 3.79 (s, 3H), 3.15 - 2.99 (m, 2H), 2.74 (s, 3H), 2.68 - 2.51 (m, 2H), 1.87 - 1.66 (m, 4H), 1.41 (s, 9H).

Step 3 - 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-2-(methylamino)benzoic acid methyl ester

To a solution of methyl 2-amino-3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]benzoate (12.1 g, 33.3 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (45.0 mL) was added methyl trifluoromethanesulfonate (8.21 g, 50.0 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was diluted with H ₂ O (300 mL) and extracted with EA (3×100 mL). The organic layer was washed with brine (3×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (12.5 g, 99% yield) as a yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (dd, J = 1.2, 8.0 Hz, 1H), 7.20 - 7.12 (m, 1H), 6.72 (t, J = 8.0 Hz, 1H), 4.23 - 3.95 (m, 1H), 3.89 (s, 3H), 3.35 - 3.23 (m, 2H), 3.01 (s, 3H), 2.82 (s, 3H), 2.70 - 2.59 (m, 2H), 1.93 - 1.85 (m, 2H), 1.78 - 1.71 (m, 2H), 1.50 (s, 9H).

Step 4 - 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-2-(methylamino)benzoic acid

To a solution of methyl 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-2-(methylamino)benzoate (12.5 g, 33.1 mmol) in MeOH (120 mL) and H ₂ O (20 mL) was added LiOH.H ₂ O (4.17 g, 99.3 mmol). The mixture was stirred at 60° C. for 12 h. Upon completion, the mixture was concentrated in vacuum. The mixture was diluted with H ₂ O (150 mL) and extracted with EA (3×50 mL). The aqueous phase was acidified to pH=5 with 1N HCl solution. The mixture was then extracted with EA (3×80 mL) and the organic layer was washed with brine (3×80 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give the title compound (11.0 g, 91% yield) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ 7.99 - 7.87 (m, 1H), 7.41 - 7.35 (m, 1H), 7.19 - 7.08 (m, 1H), 4.16 - 3.81 (m, 1H), 3.15 - 3.08 (m, 2H), 2.95 - 2.88 (m, 3H), 2.88 - 2.79 (m, 5H), 2.00 - 1.85 (m, 2H), 1.83 - 1.74 (m, 2H), 1.50 (s, 9H).

Step 5 - N-methyl-N-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]carbamate tert-butyl

To a solution of 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-2-(methylamino)benzoic acid (12.5 g, 34.3 mmol) and DIEA (13.3 g, 103 mmol) in t-BuOH (130 mL) was added DPPA (11.3 g, 41.2 mmol) at 0° C. The mixture was stirred at 90° C. for 16 h. Upon completion, the mixture was concentrated in vacuum. The mixture was diluted with H ₂ O (200 mL) and extracted with EA (3×80 mL). The organic layer was washed with brine (3×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The mixture was purified by reverse phase: (0.1% NH ₃ .H ₂ O) to give the title compound (5.4 g, 43% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 10.80 (s, 1H), 6.95 - 6.87 (m, 1H), 6.87 - 6.80 (m, 1H), 6.76 - 6.70 (m, 1H), 4.01 - 3.71 (m, 1H), 3.58 (s, 3H), 3.20 - 3.06 (m, 2H), 2.81 - 2.69 (m, 5H), 1.96 - 1.79 (m, 2H), 1.72 - 1.56 (m, 2H), 1.42 (s, 9H), LC-MS(ESI ⁺ ) m/z 361.2(M+H) ⁺ .

Step 6 - N-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamic acid tert-butyl

To a solution of tert-butyl N-methyl-N-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]carbamate (5.40 g, 14.9 mmol) in THF (60 mL) was added t-BuOK (3.03 g, 26.9 mmol) at −10° C. The mixture was stirred at −10° C. for 0.5 h. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (10.2 g, 26.9 mmol, intermediate G) in THF (50 mL) was added to the above solution. The mixture was stirred at 25° C. for 16 h. Upon completion, the mixture was quenched with saturated NH ₄ Cl solution (80 mL) and concentrated in vacuo to remove THF. The mixture was then extracted with EA (3×50 mL) and the organic layer was washed with brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo The mixture was purified by reverse phase (0.1% FA) to give the title compound (6.2 g, 69% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 7.25 - 7.18 (m, 2H), 6.97 - 6.90 (m, 2H), 6.90 - 6.80 (m, 3H), 5.57 - 5.45 (m, 1H), 4.89 - 4.74 (m, 2H), 4.07 - 3.80 (m, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.20 - 3.12 (m, 2H), 3.10 - 2.98 (m, 1H), 2.88 - 2.77 (m, 3H), 2.75 (s, 3H), 2.74 - 2.68 (m, 1H), 2.09 - 2.00 (m, 1H), 1.98 - 1.84 (m, 2H), 1.71 - 1.60 (m, 2H), 1.43 (s, 9H), LC-MS(ESI ⁺ )m/z 592.4(M+H) ⁺ .

Step 7 - 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A solution of tert-butyl N-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (2.70 g, 4.56 mmol) in TFA (30 mL) and TfOH (3.8 mL) was stirred at 60° C. for 16 h. Upon completion, the mixture was concentrated in vacuo. The residue was then adjusted to pH=3 with saturated NaHCO ₃ solution. The mixture was purified by reverse phase (0.1% FA) to give the title compound (1.6 g, 94% yield) as a blue solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.04 - 6.97 (m, 1H), 6.96 - 6.89 (m, 2H), 5.41 - 5.33 (m, 1H), 3.64 (s, 3H), 3.23 - 3.17 (m, 2H), 3.15 - 2.98 (m, 2H), 2.95 - 2.85 (m, 1H), 2.82 - 2.69 (m, 3H), 2.68 - 2.63 (m, 1H), 2.61 (s, 3H), 2.14 - 2.05 (m, 2H), 2.04 - 1.95 (m, 1H), 1.83 - 1.66 (m, 2H).

Step 8 - N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamic acid tert-butyl

To a solution of 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (1.5 g, 4.04 mmol), TEA (817 mg, 8.08 mmol) in ACN (15.0 mL) was added (Boc) ₂ O (1.32 g, 6.06 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuum. The mixture was purified by silica gel column (PE:EA=1:1) to give the title compound (700 mg, 36% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.01 - 6.91 (m, 2H), 6.90 - 6.83 (m, 1H), 5.45 - 5.27 (m, 1H), 3.97 - 3.76 (m, 1H), 3.64 (s, 3H), 3.20 - 3.10 (m, 2H), 2.95 - 2.83 (m, 1H), 2.82 - 2.76 (m, 2H), 2.74 (s, 3H), 2.73 - 2.64 (m, 1H), 2.64 - 2.56 (m, 1H), 2.04 - 1.98 (m, 1H), 1.95 - 1.83 (m, 2H), 1.70 - 1.58 (m, 2H), 1.41 (s, 9H), LC-MS(ESI ⁺ )m/z 472.3(M+H) ⁺ .

Step 9 - 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methylcarbamate (500 mg, 1.06 mmol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 6.00 mL). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to provide the title compound (430 mg, 99% yield, HCl) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 8.96 (s, 1H), 7.04 - 6.97 (m, 1H), 6.97 - 6.89 (m, 2H), 5.44 - 5.30 (m, 1H), 3.64 (s, 3H), 3.26 - 3.14 (m, 2H), 3.14 - 3.02 (m, 1H), 2.98 - 2.84 (m, 1H), 2.81 - 2.72 (m, 2H), 2.70 - 2.60 (m, 2H), 2.60 - 2.56 (m, 3H), 2.19 - 2.08 (m, 2H), 2.05 - 1.95 (m, 1H), 1.87 - 1.69 (m, 2H), LC-MS(ESI ⁺ )m/z 372.2(M+H) ⁺ .

3-[3-Methyl-4-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate EH)

Step 1 - 4-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (1.43 g, 3.51 mmol, HCl, intermediate EG) and tert-butyl 4-formylpiperidine-1-carboxylate (822 mg, 3.86 mmol, CAS#137076-22-3) in a mixed solvent of THF (40 mL) and DMF (20 mL) was added KOAc (3.44 g, 35.0 mmol) and NaBH(OAc) ₃ (1.49 g, 7.01 mmol). The mixture was stirred at 25° C. for 2 h. Upon completion, the mixture was quenched with H ₂ O (1 mL), diluted with H ₂ O (30 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic liquid was concentrated in vacuum. The residue was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (HCl)-ACN]; B%: 10%-40%, 20 min) to give the title compound (1.00 g, 50% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 10.51 (s, 1H), 8.92 - 8.82 (m, 1H), 6.94 - 6.88 (m, 2H), 5.37 (dd, J = 5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 3.41 - 3.32 (m, 2H), 3.26 - 3.22 (m, 2H), 2.98 - 2.88 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.68 - 2.66 (m, 1H), 2.25 - 2.09 (m, 4H), 2.08 - 1.97 (m, 3H), 1.96 - 1.90 (m, 2H), 1.83 - 1.73 (m, 2H), 1.67 - 1.61 (m, 2H), 1.51 - 1.43 (m, 2H), 1.42 - 1.36 (m, 9H). LC-MS(ESI ⁺ )m/z 569.3(M+H) ⁺ .

Step 2 - 3-[3-methyl-4-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate (100 mg, 175 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 1.00 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (88 mg, 99% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 469.1 (M+H) ⁺ .

2-(prop-2-yn-1-yloxy)ethyl 4-methylbenzenesulfonate (Intermediate EI)

To a solution of 2-prop-2-ynoxyethanol (5 g, 49.9 mmol, CAS#3973-18-0), 4-methylbenzenesulfonyl chloride (11.4 g, 59.9 mmol) in DCM (60 mL) was added TEA (15.1 g, 149 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was quenched with sat. aq. NH ₄ Cl (60 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=8/1 to 3/1) to give the title compound (8.2 g, yield 58.11%) as a yellow oil. ^1H NMR (400 MHz, DMSO-d6) δ = 7.82-7.80(m, 2H), 7.36-7.34 (m, 2H), 4.21-4.18 (t, 2H), 4.12 (s, 2H), 3.74-3.72 (m, 2H), 2.45 (s, 3H), 2.43 (s, 1H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(2-(prop-2-yn-1-yloxy)ethyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate EJ)

A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-(2-piperazin-1-ylethyl)pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate (0.15 g, 291 umol, synthesized by steps 1-2 of Intermediate BH), 2-prop-2-ynoxyethyl 4-methylbenzenesulfonate (66.7 mg, 262 umol, Intermediate EI), Cs ₂ CO ₃ (759 mg, 2.33 mmol), and KI (9.68 mg, 58.2 umol) in DMF (6 mL) was stirred at 70° C. for 12 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 0:1) to give the title compound (0.07 g, 36% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 597.4 (M+H) ⁺ .

3-[5-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate EK)

Step 1 - tert-butyl N-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (3.00 g, 12.0 mmol), 3-bromoprop-1-yne (1.72 g, 14.4 mmol, 1.24 mL), TBAI (356 mg, 962 umol), KI (299 mg, 1.81 mmol) and KOH (675 mg, 12.0 mmol) in THF (30 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 25 °C under _N2 atmosphere for 16 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (2.50 g, 72% yield) as a pale yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 5.05 (s, 1H), 4.22 (d, J = 2.4 Hz, 2H), 3.76 - 3.60 (m, 8H), 3.55 (t, J = 5.2 Hz, 2H), 3.35 - 3.27 (m, 2H), 2.44 (t, J = 2.4 Hz, 1H), 1.47 (s, 9H).

Step 2 - N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate tert-butyl

A mixture of tert-butyl N-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]carbamate (849 mg, 2.96 mmol), 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6 _- dione (500 mg, 1.48 mmol, Intermediate J), Pd( _PPh3 ) _2Cl2 (311 mg, 443 umol), CuI (84 mg, 443 umol) and TEA (2.69 g, 26.6 mmol, 3.70 mL) in DMF (15 mL) was degassed and purged with _N2 three times. This mixture was then stirred at 80° C. under _N2 atmosphere for 3 h. Upon completion, the mixture was concentrated in vacuo to provide a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (400 mg, 49% yield) as a pale yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.33 (s, 1H), 7.21 - 7.12 (m, 2H), 6.77 - 6.71 (m, 1H), 5.39 (dd, J = 5.2, 12.8 Hz, 1H), 4.40 (s, 2H), 3.68 - 3.62 (m, 2H), 3.61 - 3.56 (m, 2H), 3.55 - 3.47 (m, 6H), 3.35 (s, 3H), 3.07 (q, J = 6.0 Hz, 2H), 2.96 - 2.80 (m, 1H), 2.72 - 2.58 (m, 2H), 2.08 - 1.99 (m, 1H), 1.37 (s, 9H).

Step 3 - N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 734 umol) in THF (100 mL) was added Pd/C (300 mg, 10 wt%) and Pd(OH) ₂ /C (300 mg, 10 wt%). The mixture was stirred at 20° C. under H ₂ (15 psi) atmosphere for 4 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (270 mg, 67% yield) as a pale yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.07 (s, 1H), 7.08 - 6.96 (m, 2H), 6.87 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 5.34 (dd, J = 5.2, 12.4 Hz, 1H), 3.69 - 3.35 (m, 15H), 3.09 - 3.01 (m, 2H), 2.97 - 2.81 (m, 1H), 2.77 - 2.57 (m, 4H), 2.08 - 1.94 (m, 1H), 1.89 - 1.71 (m, 2H), 1.37 (s, 9H).

Step 4 - 3-[5-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate (270 mg, 492 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was then stirred at 25° C. for 3 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (220 mg, 92% yield) as a pale yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.86 (s, 3H), 7.07 - 6.97 (m, 2H), 6.91 - 6.84 (m, 1H), 5.40 - 5.29 (m, 1H), 3.61 (t, J = 5.2 Hz, 2H), 3.59 - 3.56 (m, 4H), 3.55 - 3.53 (m, 2H), 3.52 - 3.48 (m, 2H), 3.43 - 3.40 (m, 2H), 3.33 (s, 3H), 3.02 - 2.84 (m, 3H), 2.76 - 2.58 (m, 4H), 2.05 - 1.97 (m, 1H), 1.87 - 1.73 (m, 2H).

(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(4-(prop-2-yn-1-yloxy)butyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate EL)

A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-(2-piperazin-1-ylethyl)pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate (0.5 g, 971 umol, synthesized by steps 1-2 of intermediate BH), 4-prop-2-ynoxybutyl 4-methylbenzenesulfonate (246 mg, 874 umol, CAS# 1125737-76-9), Cs ₂ CO ₃ (1.58 g, 4.86 mmol), and KI (32.2 mg, 194 umol) in DMF (10 mL) was stirred at 70° C. for 4 h. Upon completion, the mixture was quenched with sat. NH ₄ Cl (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (40 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 1/2) to give the title compound (180 mg, yield 27%) as a yellow solid. LC-MS (ESI ⁺ ) m/z 615.8 (M+H) ⁺ .

Benzyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (Intermediate EM)

To a solution of 2-(2-prop-2-ynoxyethoxy)ethanamine (0.5 g, 3.49 mmol, CAS#944561-44-8) in DCM (8 mL) was added TEA (389 mg, 3.84 mmol) and benzyl carbonochloridate (655 mg, 3.84 mmol). The mixture was stirred at 25° C. for 12 h. Upon completion, the reaction mixture was poured into water (10 ml) and then the solution was extracted with DCM (10 ml×3). The organic layer was washed with brine (10 ml×3), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) to give the title compound (850 mg, 82% yield) as a white oil. LC-MS (ESI ⁺ ) m/z 278.0 (M+H) ⁺ .

3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate EN)

Step 1 - (2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)benzyl carbamate

To a solution of benzyl N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (850 mg, 3.07 mmol, intermediate EM) in THF (7 mL) and ACN (7 mL) was added XPhos Pd G3 (778 mg, 920 umol), Cs ₂ CO ₃ (5.99 g, 18.4 mmol) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.55 g, 4.60 mmol, intermediate J). The mixture was stirred at 60 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was diluted with water and extracted with DCM (10 mL x 3). The organic layer was washed with brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=6/1 to 2/1) to give the title compound (1.2 g, 50% yield) as a yellow solid: LC-MS (ESI+) m/z 535.3 (M+H) ⁺ .

Step 2 - 3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of benzyl N-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate (1.2 g, 2.24 mmol) in THF (30 mL) was added Pd/C (2.38 g, 10 wt%). The mixture was stirred at 25° C. under H ₂ atmosphere (15 PSI) for 4 h. Upon completion, the reaction mixture was filtered and then the solution was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give the title compound (90 mg, 10% yield) as a white solid. LC-MS (ESI+) m/z 405.2 (M+H) ⁺ .

2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (Intermediate EO)

To a solution of 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethanol (5 g, 21.5 mmol, CAS#87450-10-0) in DCM (50 mL) was added TEA (6.53 g, 64.6 mmol) and TosCl (4.51 g, 23.7 mmol). The mixture was stirred at 25° C. for 12 h. Upon completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (30 mL×3). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=4/1 to 1/1) to give the title compound (6.8 g, 60% yield) as a white oil. LC-MS (ESI+) m/z 386.9 (M+H) +.

2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid (Intermediate EP)

Step 1 - 2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylate methyl

To a solution of 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (6.8 g, 17.6 mmol, intermediate EO) in DMF (50 mL) was added KI (292 mg, 1.76 mmol) and Cs ₂ CO ₃ (11.5 g, 35.2 mmol) and 1H-pyrazole-5-carboxylate methyl (2.66 g, 21.1 mmol). The mixture was stirred at 70° C. for 2 h. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc (60 mL×3). The organic layer was washed with brine (50 mL×3), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=6/1 to 1/1) to give the title compound (3.7 g, 45% yield) as a white oil. LC-MS (ESI+) m/z 341.5 (M+H) ⁺ .

Step 2 - 2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid

To a solution of methyl 2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylate (3.7 g, 10.9 mmol) in MeOH (4 mL), THF (4 mL), and H ₂ O (4 mL) was added LiOH.H ₂ O (1.82 g, 43.5 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the pH of the mixture was adjusted to 5 with 1 M HCl and then extracted with EtOAc (10 mL×3). The organic layer was washed with brine (20 mL×3) and concentrated under reduced pressure to give the title compound (2.6 g) as a white oil. LC-MS (ESI+) m/z 327.2 (M+H) ⁺ .

N-Isopropylcarbamate [(1S,3R)-3-[1-tert-butyl-5-[[2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] (Intermediate EQ)
To a solution of 2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid (0.6 g, 2 mmol, intermediate EP) in ACN (6 mL) was added _T3P (3.16 g, 4.96 mmol, 50% solution) and DIEA (1.07 g, 8.27 mmol, 1.44 mL) and N-isopropylcarbamate [(1S,3R)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (510 mg, 1.65 mmol, intermediate CB). The mixture was stirred at 60° C. for 12 h. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (6 mL×3). The organic layer was washed with brine (6 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=6/1 to 1/2) to give the title compound (240 mg, 23% yield) as a yellow oil. LC-MS (ESI+) m/z 617.4 (M+H) ⁺ .

((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl) tert-butyl carbamate (CAS# 2095244-42-9) (Intermediate ER)

1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid (intermediate ES)

Step 1 - 11-(benzyloxy)undecane-1-ol

To a suspension of NaH (1.17 g, 29.2 mmol, 60% dispersion in mineral oil) in DMF (30 mL) was slowly added a solution of undecane-1,11-diol (5 g, 26.5 mmol, CAS#765-04-8) in DMF (20 mL) at −10° C. under nitrogen. The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. Next, the reaction mixture was cooled to 0° C. and then BnBr (4.09 g, 23.9 mmol, 2.84 mL) was added dropwise. The reaction mixture was allowed to warm to 25° C. and stirred for an additional 16 h. Upon completion, it was quenched with saturated aqueous NH ₄ Cl (20 mL) at 0° C. and the resulting mixture was extracted with EtOAc (30×3 mL), washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , PE:EtOAc = 5:1) to give the title compound (3.7 g, 50% yield) as a ^white gum.1H NMR (400 MHz, DMSO-d6) δ = 7.45 - 7.17 (m, 5H), 4.44 (s, 2H), 4.32 (t, J = 5.2 Hz, 1H), 3.45 - 3.34 (m, 4H), 1.56 - 1.48 (m, 2H), 1.40 (br t, J = 6.4 Hz, 2H), 1.24 (s, 14H).

Step 2 - 11-(benzyloxy)undecyl 4-methylbenzenesulfonate

To a solution of 11-(benzyloxy)undecan-1-ol (3.7 g, 10.1 mmol) and TEA (1.43 g, 14.1 mmol, 1.97 mL) in DCM (19 mL) and DMF (19 mL) was added TosCl (2.89 g, 15.2 mmol) at 0 °C under N ₂ , then the mixture was stirred at 25 °C for 12 h. Upon completion, the reaction mixture was quenched with saturated aqueous NaHCO ₃ (30 mL) at 0 °C and extracted with DCM (10 × 3 mL). The combined organic layers were washed with brine (10 × 3 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 25/1 to 5/1) to give the title compound (1.3 g, 30% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO-d6) δ = 12.47 - 12.04 (m, 1H), 8.28 - 8.18 (m, 1H), 7.77 (s, 1H), 7.43 - 7.12 (m, 5H), 4.43 (s, 2H), 4.24 - 4.07 (m, 3H), 3.40 (t, J = 6.4 Hz, 2H), 1.75 (quin, J = 7.2 Hz, 2H), 1.51 (quin, J = 6.8 Hz, 2H), 1.22 (br s, 12H).

Step 3 - 1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxylate methyl

To a solution of 1H-pyrazole-4-methyl carboxylate (395 mg, 3.14 mmol) and 11-(benzyloxy)undecyl 4-methylbenzenesulfonate (1.3 g, 2.61 mmol) in DMF (7.8 mL) was added Cs ₂ CO ₃ (1.70 g, 5.23 mmol) and KI (43.4 mg, 261 umol) at 0° C. under nitrogen flow. The reaction was then stirred at 70° C. under nitrogen atmosphere for 16 h. Upon completion, the reaction mixture was extracted with H ₂ O (20 mL) and with EtOAc (40×3 mL). The organic layer was washed with brine (25×3 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 10/1) to give the title compound (1.3 g) as a yellow oil. LC-MS (ESI ⁺ ) m/z 387.7 (M+H) ⁺ .

Step 4 - 1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid

To a solution of 1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-methyl carboxylate (1.3 g, 3.36 mmol) in THF (18 mL), H ₂ O (3 mL) and MeOH (3 mL) was added LiOH (161 mg, 6.73 mmol) and the mixture was then stirred at 40° C. for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) and extracted with EtOAc (10×3 mL). The pH of the aqueous phase was adjusted to 3-4 by addition of 2M HCl and the mixture was then extracted with EtOAc (10×3 mL). The combined organic layers were washed with brine (10×3 mL), dried over Na ₂ SO ₄ and evaporated to give the title compound (0.7 g) as a white solid. LC-MS (ESI ⁺ ) m/z 373.4 (M+H) ⁺ .

11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl-4-methylbenzenesulfonate (intermediate ET)

Step 1 - Isopropylcarbamate (1R,3S)-3-(5-(1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl

To a solution of 1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid (650 mg, 1.74 mmol, Intermediate ES) and (1R,3S)-3-(5-amino-1-isopropyl-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (357 mg, 1.16 mmol, Intermediate U) in ACN (13 mL) was added DIEA (749 mg, 5.80 mmol) and _T3P (1.48 g, 2.32 mmol, 50% solution), then the mixture was stirred at 80° C. for 16 h. Upon completion, the reaction mixture was quenched with _H2O (20 mL) and extracted with EtOAc (10×3 mL). The combined organic layers were washed with brine (10×3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by re-MPLC (water (0.225% FA)-ACN) to give the title compound (160 mg, 20% yield) as a yellow liquid. LC-MS (ESI ⁺ ) m/z 663.5 (M+H) ⁺ .

Step 2 - Isopropylcarbamate (1R,3S)-3-(1-(tert-butyl)-5-(1-(11-hydroxyundecyl)-1H-pyrazole-4-carboxamide)-1H-pyrazol-3-yl)cyclopentyl

To a solution of (1R,3S)-3-(5-(1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (130 mg, 196 umol) in EtOH (2 mL) was added Pd/C (13 mg, 35.3 umol, 10 wt %) under H ₂ (15 PSI). The mixture was then stirred at 25° C. for 17 h. Upon completion, it was filtered and concentrated to give the title compound (75 mg) as a white solid. LC-MS (ESI ⁺ ) m/z 573.9 (M+H) ⁺ .

Step 3 - 4-Methylbenzenesulfonic acid 11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl

To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(11-hydroxyundecyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 87.3 umol) in DCM (1 mL) was added TEA (26.5 mg, 261 umol). Then 4-methylbenzenesulfonyl chloride (19.9 mg, 104 umol) was added and the mixture was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with NaHCO ₃ (aq, 20 mL) at 20° C., then diluted with EtOAc (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (120 mg) as a yellow solid: LC-MS (ESI ⁺ ) m/z 727.5 (M+H) ⁺ .

2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid (Intermediate EU)

Step 1 - 2-(2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)methyl acetate

To a solution of 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (3.7 g, 11 mmol, synthesized by step 1 of intermediate BE) and methyl 2-(2-hydroxyphenyl)acetate (1.98 g, 11.8 mmol) in DMF (50 mL) was added Cs ₂ CO ₃ (17.6 g, 54.0 mmol) and KI (179.3 mg, 1.08 mmol) at 0° C. under nitrogen flow. The reaction was then stirred at 60° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into water (70 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with brine (50 mL×2), dried over sodium sulfate, filtered to obtain the filtrate, and concentrated to obtain a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:25) to give the title compound (2.2 g, 60.5% yield) as a colorless oil: LC-MS (ESI ⁺ ) m/z 359.1 (M+Na) ⁺ .

Step 2 - 2-(2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid

To a solution of methyl 2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]phenyl]acetate (2.2 g, 6.54 mmol) in THF (22 mL), methanol (11 mL) and H ₂ O (11 mL) was added LiOH.H ₂ O (1.10 g, 26.1 mmol) at 20° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into ice water (50 mL) and acidified to pH=4 with 2N hydrochloric acid. The mixture was then extracted with ethyl acetate (70 mL×2). The combined organic phase was washed with brine (50 mL×2), dried over sodium sulfate, then filtered to obtain the filtrate and concentrated to give the title compound (1.5 g) as a colorless oil. LC-MS (ESI ⁺ ) m/z 345.1 (M+Na) ⁺ .

(1S,3R)-3-(1-(tert-butyl)-5-(2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate EV)

Step 1 - Isopropylcarbamate (1S,3R)-3-(1-(tert-butyl)-5-(2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetamido)-1H-pyrazol-3-yl)cyclopentyl

To a solution of 2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]phenyl]acetic acid (0.5 g, 1.55 mmol, Intermediate EU) and N-isopropylcarbamate [(1S,3R)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (478 mg, 1.55 mmol, Intermediate CB) in ACN (10 mL) was added T3P (2.96 g, 4.65 mmol, 50% solution) and DIEA (1.00 g, 7.76 mmol) at 0 °C under nitrogen flow. The reaction was then stirred at 20 °C under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2) and dried over sodium sulfate. The filtrate was then filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:30) to give the title compound (0.7 g, yield 74%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.81 (s, 1H), 7.37 - 7.29 (m, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 5.15 (br s, 1H), 4.65 (br s, 1H), 4.26 - 4.17 (m, 4H), 3.96 - 3.87 (m, 2H), 3.86 - 3.74 (m, 3H), 3.72 - 3.51 (m, 7H), 3.47 - 3.39 (m, 2H), 3.08 (quin, J = 8.4 Hz, 1H), 2.54 - 2.36 (m, 2H), 2.03 - 1.75 (m, 5H), 1.32 (s, 8H), 1.16 (dd, J = 3.1, 6.4 Hz, 6H).

(1S,3R)-3-((3S)-5-(1-methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxamido)pyrazolidine-3-yl)cyclopentyl isopropylcarbamate (Intermediate EW)

To a solution of 1-methyl-3-((nona-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid (150 mg, 539 umol, intermediate AR) and (1S,3R)-3-((3S)-5-aminopyrazolidin-3-yl)cyclopentyl isopropylcarbamate (166 mg, 539 umol, intermediate ED) in MeCN (3 mL) was added DIEA (348 mg, 2.69 mmol) and T3P (1.03 g, 1.62 mmol, 50% solution). The mixture was then stirred at 60° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (2 mL) at 20° C. and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (2 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/4 to 1/3) to give the title compound (100 mg, 30% yield) as a yellow solid: LC-MS (ESI ⁺ ) m/z 569.5 (M+H) ⁺ .

4-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (Intermediate EX)

Step 1 - 2-((4-(benzylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.46 mmol, CAS#1016636-76-2) and 4-(benzylthio)-2-methylaniline (502 mg, 2.19 mmol, intermediate M) in IPA (10 mL) was added TFA (1.66 g, 14.6 mmol), and the mixture was then stirred at 80 °C for 12 h. Upon completion, the reaction mixture was quenched with _NaHCO3 solution (20 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (25 mL x 3), dried over _{anhydrous Na2SO4} , filtered, and concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1-3/1) to give the title compound (440 mg, 56% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.88 (s, 1H), 7.43 - 7.20 (m, 8H), 5.82 - 5.62 (m, 1H), 4.23 (s, 2H), 2.55 (s, 3H), 2.17 (s, 3H), 2.10 - 2.04 (m, 2H), 1.62 (br s, 4H), 1.40 (br s, 2H) ^; LC-MS(ESI ⁺ )m/z 536.9(M+H) ⁺ .

Step 2 - 4-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride

To a solution of 2-((4-(benzylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, 747 umol) in AcOH (10 mL) and HCl (0.3 mL) was added NCS (399 mg, 2.99 mmol) at 0° C., then the mixture was stirred at 0-25° C. for 30 min. Upon completion, the reaction mixture was quenched with water (20 mL) and extracted with DCM (10 mL×3). The organic layer was washed with brine (25 mL×3), dried over anhydrous Na ₂ SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (300 mg, 79% yield) as a pink solid. ^1H NMR (400 MHz, DMSO-d6) δ = 9.45 (s, 1H), 8.89 (s, 1H), 7.48 (s, 1H), 7.44 - 7.35 (m, 2H), 5.83 - 5.72 (m, 1H), 2.55 (s, 3H), 2.23 (s, 3H), 2.14 - 2.03 (m, 2H), 1.99 (s, 2H), 1.91 (s, 1H), 1.77 - 1.62 (m, 4H), 1.51 - 1.39 (m, 2H), 1.26 - 1.13 (m, 2H); LC-MS(ESI ⁺ ) m/z 513.2(M+H) ⁺ .

Benzyl 3,6,9,12-tetraoxapentadec-14-yn-1-ylcarbamate (intermediate EY)

To a solution of 3,6,9,12-tetraoxapentadeca-14-yn-1-amine (3 g, 12.97 mmol, CAS#1013921-36-2) in DCM (20 mL) was added TEA (1.44 g, 14.3 mmol). A solution of benzyl carbonochloridate (2.43 g, 14.3 mmol) was added to the mixture at 0° C. The mixture was stirred at 0-20° C. for 12 h. Upon completion, the reaction mixture was quenched by addition of NaHCO ₃ (sat., aqu, 20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (20 mL×3), dried over Na ₂ SO ₄ and evaporated. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (4.4 g, 93% yield) as a white gum: ¹ H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.28 (m, 5H), 7.24 (br t, J = 5.6 Hz, 1H), 5.01 (s, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.55 - 3.52 (m, 4H), 3.50 (s, 8H), 3.44 - 3.38 (m, 3H), 3.19 - 3.08 (m, 2H).

3-(5-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate EZ)

Step 1 - (15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)benzyl carbamate

To a solution of benzyl 3,6,9,12-tetraoxapentadeca-14-yn-1-ylcarbamate (2.2 g, 6.02 mmol, intermediate EY) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (3.05 g, 9.03 mmol, intermediate J) in THF (10 mL) and ACN (10 mL) was added XPhos Pd G3 (1.53 g, 1.81 mmol) and Cs ₂ CO ₃ (11.8 g, 36.1 mmol) under N _2. The mixture was stirred at 20-60 °C for 12 h. Upon completion, the reaction mixture was quenched with sat. NH ₄ Cl (20 mL) and extracted with EtOAC (30 mL x 2). The combined organic layers were washed with brine ( ₁₀ mL x 3), dried over _Na2SO4 and evaporated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250 x 50 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 28%-55%, 18 min) to give the title compound (2.56 g, 68% yield) as a white gum. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.37 - 7.29 (m, 6H), 7.29 - 7.25 (m, 1H), 7.19 - 7.11 (m, 2H), 5.39 (dd, J = 5.6, 12.8 Hz, 1H), 5.01 (s, 2H), 4.39 (s, 2H), 3.66 - 3.61 (m, 2H), 3.60 - 3.55 (m, 2H), 3.54 - 3.48 (m, 8H), 3.41 (t, J = 6 Hz, 2H), 3.34 (s, 3H), 3.14 (q, J = 5.6 Hz, 2H), 2.94 - 2.83 (m, 1H), 2.76 - 2.57 (m, 2H), 2.08 - 2.00 (m, 1H).

Step 2 - 3-(5-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of benzyl N-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1 g, 2 mmol) in THF (5 mL) was added Pd/C (400 mg, 642 umol, 10 wt%) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 several times. The reaction was stirred at 20°C under _H2 atmosphere (15 PSI) for 17 h. Upon completion, the mixture was filtered and concentrated to give the title compound (690 mg) as a white gum. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.11 - 7.97 (m, 1H), 7.77 (br s, 1H), 7.44 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 - 6.97 (m, 1H), 6.90 - 6.80 (m, 1H), 5.33 (br dd, J = 5.2, 12.6 Hz, 1H), 4.81 (br dd, J = 4.8, 10.8 Hz, 1H), 3.54 - 3.45 (m, 8H), 3.39 (br d, J = 4.4 Hz, 2H), 3.34 (br s, 3H), 2.70 - 2.58 (m, 3H), 2.18 (s, 1H), 2.04 - 1.93 (m, 1H), 1.81 (br s, 2H), 1.36 (s, 2H).

(1S,3R)-3-(1-(tert-butyl)-5-(1-(undec-10-yn-1-yl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate FA)

To a solution of 1-undec-10-ynylpyrazole-4-carboxylic acid (500 mg, 1.91 mmol, intermediate Y) and N-isopropylcarbamic acid [(1S,3R)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl] (490 mg, 1.59 mmol, intermediate CB) in ACN (8 mL) was added DIEA (1.03 g, 7.94 mmol, 1.38 mL) and T3P (3.03 g, 4.76 mmol) dropwise in one portion at 20 °C. The mixture was then stirred at 60 °C for 10 h. Upon completion, the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, elution with a gradient of 0-30% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound (325 mg, 37% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 553.4 (M+H) ⁺ .

(2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecane-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate FB)

Step 1 - ((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)carbamate tert-butyl

(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (233 mg, 542 umol, CAS# 1448189-80-7), 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetic acid (200 mg, 651 umol, CAS# 462100-06-7), DIEA (350 mg, 2.71 mmol), and HATU (247 mg, 651 umol) in DMF (10 mL) were added at 0° C. The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH=10:1 to 2:1) to give the title compound (380 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m/z 620.4 (M+H) ⁺ .

Step 2 - (2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecane-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Tert-butyl ((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)carbamate (0.19 g, 260 umol) in HCl/dioxane (2 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated in vacuo to afford the title compound (150 mg, 83% yield) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 11.08-11.04 (m, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.77-7.60 (m, 5H), 7.02-6.84 (m, 3H), 6.34-6.31 (d, J=9.2, 1H), 5.69-564(m, 1H), 5.35-5.30 (m, 1H), 3.50-3.48 (m, 6H), 3.47-3.41 (m, 5H), 3.37-3.30 (m, 6H), 2.90 (s, 2H), 2.63-2.52 (m, 4H), 2.32 (s, 3H), 1.81-1.78 (m, 5H), 1.64-1.43 (m, 6H).

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (Intermediate FC)

Step 1 - N-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate tert-butyl

To a solution of 2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (568 mg, 1.62 mmol, CAS#876345-13-0), (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (580 mg, 1.35 mmol, CAS#1448189-80-7) in DMF (10 mL) was added DIEA (870 mg, 6.74 mmol) and HATU (614.64 mg, 1.62 mmol) at 0° C. The mixture was then stirred at 25° C. for 2 h. Upon completion, the reaction mixture was quenched with 20 mL of water at 0° C. and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give the title compound (800 mg, yield 78%) as a yellow oil. ^1H NMR (400 MHz, DMSO-d6) δ = 9.01 - 8.96 (m, 1H), 8.59 (br t, J = 5.6 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.42 - 7.36 (m, 4H), 7.36 - 7.36 (m, 1H), 6.73 (br t, J = 4.8 Hz, 1H), 5.15 (d, J = 3.6 Hz, 1H), 4.56 (d, J = 9.2 Hz, 1H), 4.37 - 4.36 (m, 1H), 4.48 - 4.36 (m, 1H), 4.29 - 4.20 (m, 1H), 4.01 - 3.90 (m, 2H), 3.70 - 3.43 (m, 16H), 3.17 (d, J = 5.2 Hz, 1H), 3.04 (q, J = 5.6 Hz, 2H), 2.46 - 2.43 (m, 3H), 2.06 (br dd, J = 7.6, 12.8 Hz, 1H), 1.90 (ddd, J = 4.0, 8.4, 12.8 Hz, 1H), 1.36 (s, 9H), 0.99 - 0.89 (m, 9H); LC-MS(ESI ⁺ )m/z 764.4(M+H) ⁺ .

Step 2 - (2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of tert-butyl N-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 524 umol) in DCM (2 mL) was added HCl/dioxane (4 mL, 4 M) and the mixture was then stirred for 1.5 h at 25° C. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (200 mg, 55% yield, HCl) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.04 - 7.75 (m, 3H), 7.52 - 7.46 (m, 1H), 7.40 (s, 4H), 4.56 (d, J = 9.4 Hz, 1H), 4.47 - 4.37 (m, 2H), 4.36 (br s, 1H), 4.30 - 4.21 (m, 1H), 3.98 (s, 2H), 3.63 - 3.57 (m, 8H), 3.56 - 3.52 (m, 8H), 2.98 - 2.92 (m, 2H), 2.45 (s, 3H), 2.13 - 2.01 (m, 1H), 1.90 (ddd, J = 4.4, 8.8, 13.2 Hz, 1H), 0.98 - 0.91 (m, 9H). LC-MS(ESI ⁺ )m/z 664.3(M+H) ⁺ .

3-[5-[3-(2-azidoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate FD)

Step 1 - 3-[5-[3-(2-hydroxyethoxy)prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 2-prop-2-ynoxyethanol (500 mg, 4.99 mmol, CAS# 3973-18-0) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.03 g, 5.99 mmol, intermediate J) in ACN (10 mL) and THF (10 mL) was added XPhos Pd G3 (845 mg, 999 umol) and Cs ₂ CO ₃ (4.88 g, 14.9 mmol). The mixture was stirred at 60 °C under nitrogen atmosphere for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl solution (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to afford the title compound (550 mg, yield 31%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 11.1 (s, 1H), 7.33 (s, 1H), 7.20 - 7.09 (m, 2H), 5.39 (dd, J = 5.6, 13.2 Hz, 1H), 4.78 - 4.52 (m, 1H), 4.39 (s, 2H), 4.03 (q, J = 7.2 Hz, 1H), 3.56 - 3.53 (m, 3H), 3.34 (s, 4H), 2.77 - 2.56 (m, 4H); LC-MS(ESI ⁺ ) m/z 358.1(M+H) ⁺ .

Step 2 - 3-[5-[3-(2-hydroxyethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 3-[5-[3-(2-hydroxyethoxy)prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (550 mg, 1.5 mmol) in THF (6 mL) was added PtO ₂ (69.9 mg, 308 umol) under H ₂ and the mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was filtered through diatomaceous earth. The organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give the title compound (300 mg, 54% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 11.08 (s, 1H), 7.04 (d, J = 1.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 1.6, 8.4 Hz, 1H), 5.33 (dd, J = 5.6, 12.8 Hz, 1H), 4.63 - 4.51 (m, 1H), 3.51 (q, J = 5.6 Hz, 2H), 3.44 - 3.35 (m, 4H), 3.30 (s, 3H), 2.95 - 2.84 (m, 1H), 2.75 - 2.57 (m, 4H), 2.05 - 1.95 (m, 1H), 1.86 - 1.76 (m, 2H); LC-MS(ESI ⁺ )m/z 362.0(M+H) ⁺ .

Step 3 - 4-Methylbenzenesulfonic acid 2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl

To a solution of 3-[5-[3-(2-hydroxyethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (150 mg, 415 umol) and TEA (126 mg, 1.25 mmol, 173 uL) in DCM (3 mL) was added TosCl (119 mg, 623 umol) and DMAP (10.1 mg, 83.0 umol) at 0 °C under _N2 . The mixture was then stirred at 25 °C for 12 h. Upon completion, the reaction mixture was quenched with _NaHCO3 solution (30 mL) at 0 °C and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to afford the title compound (179 mg, yield 84%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 11.08 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.09 - 6.92 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.33 (dd, J = 5.2, 12.8 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.58 - 3.50 (m, 2H), 3.30 (br s, 3H), 2.94 - 2.85 (m, 1H), 2.76 - 2.62 (m, 2H), 2.60 - 2.55 (m, 2H), 2.53 - 2.51 (m, 2H), 2.40 (s, 3H), 2.05 - 1.99 (m, 1H), 1.79 - 1.67 (m, 2H); LC-MS(ESI ⁺ )m/z 516.4(M+H) ⁺ .

Step 4 - 3-[5-[3-(2-azidoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl 4-methylbenzenesulfonate (170 mg, 330 umol) in DMF (2 mL) was added _NaN3 (23.6 mg, 362 umol) at 0 °C under _N2 . The mixture was then stirred at 40 °C for 12 h. Upon completion, the reaction was poured into _NaHCO3 solution (10 mL) at 0 °C and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL x ₂ ), dried over _Na2SO4 , then filtered to obtain the filtrate and concentrated to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (70 mg, 53% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 387.1 (M+H) ⁺ .

tert-Butyl 6-(2-(tosyloxy)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate FE)

Step 1 - 6-(2-(tert-butoxy)-2-oxoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 46.8 mmol, CAS#1147557-97-8), tert-butyl 2-bromoacetate (13.7 g, 70.3 mmol) and tetrabutylammonium hydrogen sulfate (1.59 g, 4.69 mmol) in toluene (10 mL) and H ₂ O (1 mL) was added NaOH (9.38 g, 234 mmol) and the mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was quenched with 100 mL of aqueous NH ₄ Cl at 0° C., then diluted with H ₂ O (100 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (11 g, 72% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.92 - 3.84 (m, 1H), 3.83 - 3.77 (m, 6H), 2.47 - 2.35 (m, 2H), 2.19 - 2.05 (m, 2H), 1.40 (s, 9H), 1.35 (s, 9H); LC-MS(ESI ⁺ )m/z 328.2(M+H) ⁺ .

Step 2 - 6-(2-hydroxyethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-(2-tert-butoxy-2-oxo-ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 30.5 mmol) in THF (150 mL) was added LiAlH ₄ (2.32 g, 61.0 mmol). The mixture was stirred at 0° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (4 mL) and NaOH (15%, 4 mL) at 0° C. and then stirred at 25° C. for 30 min. The mixture was then filtered and concentrated under reduced pressure to give the title compound (5 g) as a yellow oil. LC-MS (ESI ⁺ ) m/z 258.2 (M+H) ⁺ .

Step 3 - 6-(2-(tosyloxy)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-(2-hydroxyethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 20 mmol) in DCM (50 mL) was added TEA (5.90 g, 58.2 mmol), TosCl (4.45 g, 23.3 mmol) and DMAP (474 mg, 3.89 mmol). The mixture was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with aqueous NH ₄ Cl (50 mL), then diluted with H ₂ O (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 4/1) to give the title compound (1.8 g, 22.0% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 356.2 (M+H) ⁺ .

3-(5-(1-(2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FF)

Step 1 - 6-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (300 mg, 876 umol, Intermediate DB) and tert-butyl 6-[2-(p-tolylsulfonyloxy)ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (360 mg, 876 umol, Intermediate FE) in ACN (3 mL) was added K ₂ CO ₃ (605 mg, 4.38 mmol) and KI (14.5 mg, 87.6 umol). The mixture was stirred at 60° C. for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by prep-HPLC (FA conditions) to provide the title compound (80 mg, 15% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 582.4 (M+H) ⁺ .

Step 2 - 3-(5-(1-(2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 6-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (80 mg, 140 umol) in DCM (2 mL) was added TFA (15.6 mg, 137 umol). The mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (75 mg, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 482.4 (M+H) ⁺ .

tert-Butyl 4-prop-2-ynyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (Intermediate FG)

To a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (400 mg, 1.56 mmol, CAS#930785-40-3), K ₂ CO ₃ (646 mg, 4.68 mmol) in THF (40 mL) was added 3-bromoprop-1-yne (243 mg, 1.64 mmol). The reaction mixture was stirred at 20° C. for 24 h. Upon completion, the reaction mixture was concentrated in vacuum. The residue was diluted with H ₂ O (30 mL) and extracted with EA (3×20 mL). The organic layer was washed with brine (2×15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give the title compound (450 mg, 97% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 3.82 - 3.65 (m, 4H), 3.27 (d, J = 2.4 Hz, 2H), 3.22 - 3.10 (m, 2H), 2.55 - 2.50 (m, 2H), 2.37 (s, 2H), 2.29 - 2.26 (m, 1H), 1.99 - 1.90 (m, 2H), 1.53 - 1.45 (m, 11H).

3-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FH)

Step 1 - 3-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (7.00 g, 24.3 mmol, intermediate BZ) and HOAc (4.39 g, 73.1 mmol) in DMF (50 mL) and THF (50 mL) was added NaBH ₃ CN (6.13 g, 97.4 mmol) portionwise at 60° C., then the mixture was stirred at 60° C. for 2 h. Upon completion, the reaction was quenched with 5 mL of water and filtered, and the filtrate was concentrated. The residue was purified by reverse phase (FA) to give the title compound (5.00 g, 70% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.13 - 6.89 (m, 3H), 5.38 (d, J = 5.4, 12.4 Hz, 1H), 4.74 (s, 2H), 3.62 (s, 3H), 2.95 - 2.86 (m, 1H), 2.78 - 2.60 (m, 2H), 2.10 - 1.95 (m, 1H).

Step 2 - 3-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of 3-[4-(hydroxymethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (5.00 g, 17.2 mmol) and pyridine (273 mg, 3.46 mmol) in THF (30 mL) and DCM (30 mL) was added SOCl ₂ (6.17 g, 51.8 mmol) and the mixture was then stirred for 12 h at 20° C. Upon completion, the reaction was concentrated to give the title compound (8.00 g, 90% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.19 - 6.99 (m, 3H), 5.32 (dd, J = 5.2, 12.4 Hz, 1H), 5.03 (s, 2H), 3.65 (s, 3H), 2.92 - 2.80 (m, 1H), 2.73 - 2.59 (m, 2H), 2.10 - 1.98 (m, 1H).

Benzyl 4-(4-(prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate FI)

Step 1 - 4-(1-((benzyloxy)carbonyl)piperidin-4-yl)piperazine-1-carboxylate tert-butyl

To a solution of benzyl 4-oxopiperidine-1-carboxylate (5 g, 20 mmol, CAS# 19099-93-5) and tert-butyl piperazine-1-carboxylate (4.77 g, 21.4 mmol, CAS# 57260-71-6) in DMSO (25 mL) and THF (25 mL) was added KOAc (6.31 g, 64.31 mmol), 4A molecular sieves (1 g) and HOAc (3.86 g, 64.3 mmol) and the mixture was stirred for 30 minutes at 0° C. Then NaBH(OAc) ₃ (13.63 g, 64.31 mmol) was added and the mixture was stirred at 0-20° C. for 12 hours. The reaction mixture was quenched with _H2O (50 mL) at 0°C, then diluted with EtOAc (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with sat. NaCl (50 mL x ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (4 g, 46% yield) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 7.45 - 7.22 (m, 7H), 5.06 (s, 3H), 4.01 (br d, J = 13.2 Hz, 2H), 3.78 - 3.59 (m, 2H), 3.46 - 3.37 (m, 1H), 3.06 (br s, 1H), 2.92 - 2.63 (m, 2H), 2.41 (br s, 5H), 1.91 (s, 1H), 1.71 (br d, J = 12.2 Hz, 3H), 1.38 (s, 9H), 1.33 - 1.20 (m, 4H); LC-MS(ESI ⁺ ) m/z 404.5(M+H) ⁺ .

Step 2 - 4-(piperazin-1-yl)piperidine-1-carboxylate benzyl

To a solution of tert-butyl 4-(1-((benzyloxy)carbonyl)piperidin-4-yl)piperazine-1-carboxylate (100 mg, 300 umol) in DCM (1 mL) was added TFA (28.2 mg, 247 umol). The mixture was stirred at 25° C. for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (70 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 304 (M+H) ⁺ .

Step 3 - 4-(4-(prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate benzyl

To a solution of benzyl 4-(piperazin-1-yl)piperidine-1-carboxylate (2.3 g, 7.6 mmol) and 3-bromoprop-1-yne (811.63 mg, 6.82 mmol, CAS#106-96-7) in ACN (25 mL) was added K ₂ CO ₃ (10.4 g, 75.8 mmol). The mixture was stirred at 20 °C under N ₂ atmosphere for 10 h. The reaction mixture was quenched with H ₂ O (25 mL) at 25 °C, then diluted with EtOAc (25 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with sat. NaCl (25 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (0.05% NH3H2O)-ACN]; B%: 25%-55%, 10 min) to give the title compound as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 8.20 (s, 2H), 7.37 - 7.33 (m, 3H), 5.76 (s, 1H), 5.12 - 5.00 (m, 2H), 4.62 - 4.46 (m, 1H), 4.01 (br d, J = 13.0 Hz, 2H), 3.53 (br s, 1H), 3.23 (d, J = 2.4 Hz, 1H), 2.94 - 2.71 (m, 3H), 2.45 (br s, 5H), 1.75 (br d, J = 10.4 Hz, 3H), 1.29 (dq, J = 3.8, 11.8 Hz, 2H); LC-MS(ESI ⁺ ) m/z 342.4(M+H) ⁺ .

3-(3-Methyl-2-oxo-5-(3-(4-(piperidin-4-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FJ)

Step 1 - 4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate benzyl

To a solution of benzyl 4-(4-(prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (270 mg, 790 umol, Intermediate FI) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (320 mg, 948 umol, Intermediate J) in THF (1.5 mL) and ACN (1.5 mL) was added XPhos Pd _G3 (200 mg, 237 umol) and _Cs2CO3 (1.29 g, 3.95 mmol). This mixture was stirred at 60 °C under _N2 atmosphere for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl (5 mL) at 0° C., then diluted with EtOAc (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with sat. NaCl (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (380 mg, 80% yield) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 11.11 (s, 1H), 8.14 (s, 1H), 7.43 - 7.27 (m, 6H), 7.19 - 7.06 (m, 2H), 5.38 (dd, J = 5.3, 12.8 Hz, 1H), 5.05 (s, 2H), 4.01 (br d, J = 13.0 Hz, 3H), 3.48 (s, 5H), 2.93 - 2.73 (m, 4H), 2.73 - 2.58 (m, 3H), 2.44 - 2.30 (m, 2H), 2.10 - 1.94 (m, 1H), 1.75 (br d, J = 11.2 Hz, 2H), 1.28 (dq, J = 4.0, 11.8 Hz, 2H); LC-MS(ESI ⁺ )m/z 599.3(M+H) ⁺ .

Step 2 - 3-(3-methyl-2-oxo-5-(3-(4-(piperidin-4-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of benzyl 4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (310 mg, 520 umol) in THF (15 mL) was added Pd/C (548 mg, 517 umol, 10 wt%). The mixture was stirred at 20 °C under _H2 atmosphere for 4 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 0%-20%, 10 min) to give the title compound (80 mg, 33% yield) as a white oil. LC-MS (ESI ⁺ ) m/z 469.4 (M+H) ⁺ .

3-(4-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FK)

Step 1 - 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate tert-butyl

To a solution of tert-butyl 4-prop-2-ynyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (450 mg, 1.53 mmol, intermediate FG), 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (344 mg, 1.02 mmol, intermediate H) in DMF (5 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (143 mg, 203 umol), CuI (38.8 mg, 203 umol) and Cs ₂ CO ₃ (1.33 g, 4.08 mmol). The reaction mixture was stirred at 80° C. for 3 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase: (0.1% FA) to give the title compound (400 mg, 71% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.12 (s, 1H), 7.20 - 7.09 (m, 2H), 7.06 - 6.99 (m, 1H), 5.47 - 5.32 (m, 1H), 3.70 - 3.62 (m, 5H), 3.61 - 3.54 (m, 4H), 3.11 - 2.99 (m, 2H), 2.94 - 2.83 (m, 1H), 2.78 - 2.68 (m, 1H), 2.66 - 2.57 (m, 1H), 2.43 - 2.35 (m, 2H), 2.08 - 1.98 (m, 1H), 1.89 - 1.75 (m, 2H), 1.46 - 1.28 (m, 13H), LC-MS(ESI ⁺ )m/z 552.4(M+H) ⁺ .

Step 2 - 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate tert-butyl

To a solution of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 181 umol) in THF (10.0 mL) was added Pd/C (50 mg) and Pd(OH) ₂ /C (50 mg). The reaction mixture was stirred at 25° C. under H ₂ (15 psi) for 3 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 99% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.00 - 6.93 (m, 2H), 6.92 - 6.88 (m, 1H), 5.43 - 5.31 (m, 1H), 3.64 - 3.59 (m, 3H), 3.57 (s, 3H), 3.55 - 3.49 (m, 1H), 3.13 - 2.98 (m, 2H), 2.96 - 2.83 (m, 3H), 2.76 - 2.68 (m, 1H), 2.65 - 2.60 (m, 1H), 2.32 - 2.25 (m, 3H), 2.24 - 2.19 (m, 2H), 2.05 - 1.96 (m, 1H), 1.85 - 1.68 (m, 5H), 1.45 - 1.40 (m, 2H), 1.36 (s, 9H).

Step 3 - 3-[3-methyl-4-[3-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 179 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 3.00 mL). The reaction mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to provide the title compound (88.0 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI ⁺ ) m/z 456.2 (M+H) ⁺ .

3-[3-Methyl-2-oxo-5-[3-(4-piperidyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate FL)
Step 1 - tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]piperidine-1-carboxylate To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (350 mg, 1.04 mmol, Intermediate J) and tert-butyl 4-propa-2-ynoxypiperidine-1-carboxylate (371 mg, 1.55 mmol, synthesized by Step 1 of Intermediate FW) in DMF (20 mL) was _added Pd( _PPh3 ) _2Cl2 (72.6 mg, 103 umol), CuI (39.4 mg, 207 umol), Cs2CO3 (2.2 mg, _0.2 mmol), _1H2O ... (1.35 g, 4.14 mmol) and 4A molecular sieves (200 mg, 1.04 mmol) were added in one portion at 25 °C under _N2 . The reaction mixture was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was quenched at 25 °C by addition of water ( _0.5 mL) and then extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA conditions) to give the title compound (300 mg, 58% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.14 (s, 1H), 7.23 - 7.17 (m, 1H), 7.12 (d, J = 1.2 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.24 - 5.17 (m, 1H), 4.43 (s, 2H), 3.85 - 3.72 (m, 3H), 3.43 (s, 3H), 3.18 - 3.09 (m, 2H), 3.01 - 2.92 (m, 1H), 2.90 - 2.67 (m, 2H), 2.30 - 2.20 (m, 1H), 1.94 - 1.86 (m, 2H), 1.64 - 1.57 (m, 2H), 1.47 (s, 9H); LC-MS(ESI ⁺ )m/z 519.3(M+Na) ⁺ .
Step 2 - tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]piperidine-1-carboxylate To a solution of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]piperidine-1-carboxylate (300 mg, 604 umol) in THF (4 mL) was added Pd/C (50 mg, 10 wt%) and Pd(OH) ₂ /C (50 mg, 10 wt%) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 three times. The mixture was stirred at 25°C under _H2 (15 psi) for 2 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by reverse phase (FA conditions) to give the title compound (300 mg, 84% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.24 (s, 1H), 6.95 - 6.85 (m, 2H), 6.73 (d, J = 8.2 Hz, 1H), 5.26 - 5.18 (m, 1H), 3.81 - 3.73 (m, 2H), 3.49 - 3.42 (m, 6H), 3.15 - 3.05 (m, 2H), 2.99 - 2.82 (m, 2H), 2.75 (t, J = 7.6 Hz, 3H), 2.28 - 2.19 (m, 1H), 1.95 - 1.77 (m, 4H), 1.53 (d, J = 8.8 Hz, 2H), 1.47 (s, 9H); LC-MS(ESI ⁺ )m/z 401.0(M+H −100) ⁺ .
Step 3 - 3-[3-Methyl-2-oxo-5-[3-(4-piperidyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione To a mixture of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]piperidine-1-carboxylate (270 mg, 539 umol) in DCM (4 mL) was added TFA (1.84 g, 16.2 mmol) at 25°C. The mixture was stirred at 25°C for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by reverse phase (TFA condition) to provide the title compound (162 mg, 58% yield, TFA salt) as a yellow solid. LC-MS (ESI+) m/z 401.0 (M+H) ⁺ .

tert-Butyl 6-(2-aminoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate FM)

Step 1 - 6-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-[2-(p-tolylsulfonyloxy)ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (1.8 g, 4.4 mmol, Intermediate FE) in DMF (20 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (1.22 g, 6.56 mmol). The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was washed with H ₂ O (20 mL) at 20° C. and then filtered under reduced pressure to give the title compound (1 g) as a white solid. LC-MS (ESI ⁺ ) m/z 387.1 (M+H) ⁺ .

Step 2 - 6-(2-aminoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1 mmol) in EtOH (6 mL) was added NH ₂ NH ₂ .H ₂ O (259 mg, 5.18 mmol). The mixture was stirred at 50° C. for 2 h. Upon completion, the residue was purified by recrystallization from DCM (10 mL) at 20° C., then filtered and concentrated under reduced pressure to give a residue. The residue was purified by recrystallization from DCM (10 mL) at 0° C., then filtered and dried under reduced pressure to give the title compound (240 mg, 90% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 257.1 (M+H) ⁺ .

N-(2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide (Intermediate FN)

Step 1 - 6-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-(2-aminoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 800 umol, Intermediate FM) in DCM (5 mL) was added DIEA (302 mg, 2.34 mmol) and 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (353 mg, 780 umol, Intermediate CW). The mixture was stirred at 20° C. for 10 min. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (400 mg) as a yellow oil. LC-MS (ESI ⁺ ) m/z 673.3 (M+H) ⁺ .

Step 2 - 6-(2-(4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 742 umol) and TEA (191 mg, 1.90 mmol) in THF (10 mL) was added TEA (191.98 mg, 1.90 mmol) and Pd/C (10 wt%, 500 mg) under N _2. The suspension was degassed under reduced pressure and purged with H ₂ several times. The mixture was then stirred under H ₂ (15 psi) at 20 °C for 0.5 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (300 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 639.4 (M+H) ⁺ .

Step 3 - N-(2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide

To a solution of tert-butyl 6-[2-[[4-[(8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 234.82 umol) in DCM (4 mL) was added TFA (693 mg, 6.08 mmol). The mixture was stirred at 20° C. for 0.5 h. Upon completion, the reaction mixture was filtered under reduced pressure to give the title compound (150 mg, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 539.2 (M+H) ⁺ .

(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propiolaldehyde (Intermediate FO)

Step 1 - 3-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3 g, 8.87 mmol, intermediate J), tert-butyl-dimethyl-prop-2-ynoxy-silane (4.53 g, 26.6 mmol), TEA (4.49 g, 44.3 mmol), Pd( _PPh3 ) ₄ (1.03 g, 887 umol) and CuI (337 mg, 1.77 mmol) in DMSO (50 mL) was degassed and purged with _N2 three times. This mixture was then stirred at 85 °C under _N2 atmosphere for 12 h. Upon completion, the reaction mixture was diluted with _H2O (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with aqueous NaCl (200 mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 10/1 _to 1/1) to give the title compound (2 g, 50% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 428.2 (M+H) ⁺ .

Step 2 - 3-(5-(3-hydroxyprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of 3-[5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (300 mg, 700 umol) in DMSO (5 mL) was added CsF (532 mg, 3.51 mmol). The mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched with HCl (1M, 10 mL) at 0° C., then diluted with H ₂ O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with aqueous NaCl (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (200 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 314.1 (M+H) ⁺ .

Step 3 - (3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propiolaldehyde

To a solution of 3-[5-(3-hydroxyprop-1-ynyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (200 mg, 638 umol) in DCM (5 mL) and DMSO (2 mL) was added DMP (541 mg, 1.28 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with aqueous NaCl (20 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (120 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 312.1 (M+H) ⁺ .

tert-Butyl 9-(2-(tosyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (Intermediate FP)

Step 1 - 9-Hydroxy-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (3 g, 10 mmol, CAS#873924-08-4) in THF (30 mL) was added NaBH ₄ (636 mg, 16.8 mmol) in portions at 0° C., then the mixture was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl aq. (50 mL) at 20° C., then diluted with EtOAc (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (3 g, yield 99%) as a yellow solid.

Step 2 - 9-(2-(tert-butoxy)-2-oxoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (3 g, 11.1 mmol) in THF (30 mL) was added NaH (668 mg, 16.7 mmol, 60% dispersion in mineral oil) at 0° C. and the mixture was stirred at 0° C. for 1 h. Then tert-butyl 2-bromoacetate (3.26 g, 16.7 mmol, 2.47 mL) was added and the mixture was stirred at 0-20° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20° C., then diluted with 10 mL of EtOAc and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (1.4 g, 33% yield) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d6) δ = 3.95 (s, 2H), 3.26 (br s, 5H), 1.70 - 1.63 (m, 3H), 1.57 (br dd, J = 4.0, 10.0 Hz, 4H), 1.41 (s, 9H), 1.38 (s, 9H), 1.29 - 1.22 (m, 5H).

Step 3 - 9-(2-hydroxyethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-(2-(tert-butoxy)-2-oxoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (1.4 g, 3.7 mmol) in THF (15 mL) was added LiAlH ₄ (207 mg, 5.48 mmol) at 0 °C, then the mixture was stirred at 0 °C under N ₂ atmosphere for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (0.01 mL) and 15% NaOH aq (0.1 mL) at 0 °C. The mixture was then filtered and concentrated under reduced pressure to give the title compound (700 mg, 61% yield) as a colorless gum. ^1H NMR (400 MHz, DMSO-d6) δ = 4.51 (t, J = 5.2 Hz, 1H), 3.49 - 3.46 (m, 1H), 3.48 - 3.37 (m, 3H), 3.29 - 3.22 (m, 5H), 1.67 (br dd, J = 4.0, 8.8 Hz, 1H), 1.57 (br d, J = 10.4 Hz, 3H), 1.38 (s, 9H), 1.36 - 1.32 (m, 4H), 1.18 - 1.11 (m, 4H).

Step 4 - 9-(2-(tosyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-(2-hydroxyethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (700 mg, 2.23 mmol) in DCM (10 mL) was added TEA (677 mg, 6.69 mmol) and 4-methylbenzenesulfonyl chloride (637 mg, 3.35 mmol) at 0° C., then the mixture was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20° C., then diluted with EtOAc (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give the title compound (430 mg, yield 29%) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 7.78 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.11 - 4.08 (m, 2H), 3.55 - 3.51 (m, 2H), 3.29 - 3.21 (m, 5H), 2.42 (s, 3H), 1.63 - 1.46 (m, 5H), 1.38 (s, 9H), 1.31 - 1.27 (m, 2H), 1.25 - 1.21 (m, 3H), 1.11 - 1.02 (m, 2H).

tert-Butyl 9-(2-aminoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (Intermediate FQ)

Step 1 - 9-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

A solution of tert-butyl 9-(2-(tosyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (200 mg, 428 umol, Intermediate FP) and potassium 1,3-dioxoisoindolin-2-ide (119 mg, 642 umol) in DMF (1 mL) was stirred at 50° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20° C., filtered, and washed with H ₂ O (20 mL) to afford the title compound (120 mg, 63% yield) as a white solid. LC-MS (ESI+) m/z 465.1 (M+Na) ⁺ .

Step 2 - 9-(2-aminoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 270 umol) in EtOH (4 mL) was added NH ₂ NH ₂ .H ₂ O (102 mg, 2.04 mmol) and the mixture was then stirred at 50° C. for 2 h. Upon completion, the mixture was filtered and concentrated in vacuo to afford the title compound (130 mg) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 3.36 - 3.33 (m, 3H), 3.29 - 3.24 (m, 6H), 2.63 (t, J = 5.6 Hz, 2H), 1.72 - 1.64 (m, 2H), 1.61 - 1.54 (m, 2H), 1.38 (s, 9H), 1.36 - 1.32 (m, 3H), 1.28 - 1.23 (m, 3H), 1.18 - 1.09 (m, 2H).

N-(2-(3-azaspiro[5.5]undecan-9-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide (Intermediate FR)

Step 1 - 9-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-(2-aminoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 384 umol, Intermediate FQ) and DIEA (397 mg, 3.07 mmol), MS of 4A (100 mg, 384 umol) in DCM (2 mL) was added 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (191 mg, 422 umol, Intermediate CW), and then the mixture was stirred at 25 °C for 10 min. Upon completion, the reaction mixture was quenched with H ₂ O (2 mL) at 20 °C and extracted with DCM mL (2 mL × 3). The combined organic layers were washed with brine (2 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (300 mg) as a white solid: LC-MS (ESI+) m/z 729.2 (M+H) ⁺ .

Step 2 - 9-(2-(4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of Pd/C (500 mg, 471 umol, 10 wt%) in THF (3 mL) was added DIEA (106 mg, 822 umol, 143 uL) and tert-butyl 9-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (300 mg, 411 umol). The mixture was then stirred at 20° C. under H ₂ atmosphere (15 PSI) for 2 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (120 mg) as a brown solid. LC-MS (ESI+) m/z 695.2 (M+H) ⁺ .

Step 3 - N-(2-(3-azaspiro[5.5]undecan-9-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide

A solution of tert-butyl 9-(2-(4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 170 umol) in DCM (5 mL) and HCl/dioxane (4M, 1 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (100 mg) as a white solid. LC-MS (ESI+) m/z 595.2 (M+H) ⁺ .

3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propanal (Intermediate FS)

Step 1 - 3-[5-(3-hydroxyprop-1-enyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, intermediate _J ) and prop-2-en-1-ol (350 mg, 6.03 mmol) in dioxane (10.0 mL) was added _P (t-Bu) (1.20 g, 591 umol, 10 wt%), _Pd (dba) (270 mg, 295 umol) and DIPEA (496 mg, 3.84 mmol). The mixture was stirred at ₂₀ ° C. under N for 16 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to afford the title compound (750 mg, 80% yield) as a yellow solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 12.74 (s, 1H), 11.08 (s, 1H), 9.80 - 9.62 (m, 1H), 7.11 - 7.07 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.95 - 6.93 (m, 1H), 6.96 - 6.83 (m, 1H), 5.41 - 5.25 (m, 1H), 3.31 (s, 3H), 2.94 - 2.89 (m, 2H), 2.81 - 2.76 (m, 1H), 2.75 - 2.65 (m, 1H), 2.65 - 2.54 (m, 1H), 2.04 - 1.94 (m, 1H).

Step 2 - 3-[5-(3-hydroxypropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of 3-[5-[(E)-3-hydroxyprop-1-enyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (750 mg, 2.38 mmol) in THF (30.0 mL) was added PtO ₂ (54.0 mg, 237 umol). The mixture was stirred at 20° C. under H ₂ (15 psi) for 16 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to afford the title compound (220 mg, 29% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.06 - 6.96 (m, 2H), 6.90 - 6.82 (m, 1H), 5.38 - 5.27 (m, 1H), 3.45 - 3.42 (m, 2H), 3.33 (s, 3H), 2.98 - 2.78 (m, 2H), 2.76 - 2.68 (m, 1H), 2.64 - 2.60 (m, 1H), 2.59 - 2.52 (m, 1H), 2.05 - 1.93 (m, 1H), 1.83 - 1.66 (m, 2H).

Step 3 - 3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propanal

To a solution of 3-[5-(3-hydroxypropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (220 mg, 693 umol) in DCM (10.0 mL) was added DMP (352 mg, 831 umol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was quenched with saturated Na ₂ S ₂ O ₃ (30 mL) and washed with saturated NaHCO ₃ (2×30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (200 mg, 91% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 316.1 (M+H) ⁺ .

8-Cyclopentyl-2-((2-methyl-4-(piperazin-1-ylsulfonyl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate FT)

Step 1 - 4-((4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl piperazine-1-carboxylate (90.3 mg, 485 umol, CAS# 143238-38-4) in DCM (2 mL) was added DIEA (285 mg, 2.21 mmol) and 4A molecular sieves (200 mg), then 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (200 mg, 441 umol, Intermediate CW) was added and the mixture was stirred at 20° C. for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (100 mg, 38% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 603.5 (M+H) ⁺ .

Step 2 - 4-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-((4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate (180 mg, 298 umol) in THF (2 mL) was added TEA (90.6 mg, 895 umol) and Pd/C (316 mg, 298 umol). The mixture was stirred at 20° C. under H ₂ atmosphere (15 PSI) for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (100 mg, 59% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 569.3 (M+H) ⁺ .

Step 3 - 8-Cyclopentyl-2-((2-methyl-4-(piperazin-1-ylsulfonyl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

A solution of tert-butyl 4-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate (100 mg, 175 umol) in HCl/dioxane (1 mL) was stirred at 20° C. for 20 min. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (70 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 469.2 (M+H) ⁺ .

6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hex-5-ynal (Intermediate FU)

Step 1 - 3-(5-(6-hydroxyhex-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of hex-5-yn-1-ol (483 mg, 4.93 mmol) (CAS# 928-90-5) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (2 g, 5.91 mmol, intermediate J) in ACN (10 mL) and THF (10 mL) was added XPhos Pd G3 (1.25 g, 1.48 mmol) and Cs ₂ CO ₃ (8.03 g, 24.6 mmol). The mixture was then stirred at 60 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was washed with sat. The mixture was quenched with NH ₄ Cl (20 mL) at 0° C., then diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with sat. NaCl (20 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (1.3 g, 74% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 356.2 (M+H) ⁺ .

Step 2 - 6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hex-5-ynal

To a solution of 3-(5-(6-hydroxyhex-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (200 mg, 562 umol) in DCM (2 mL) was added DMP (358 mg, 844 umol) at 0° C. The mixture was stirred at 0-20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25° C., then diluted with Na ₂ SO ₃ (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with NaHCO ₃ (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 15 g SepaFlash® silica flash column, elution with a gradient of 0-100% ethyl acetate/petroleum ether at 20 mL/min) to afford the title compound (80 mg, 40% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 354.2 (M+H) ⁺ .

(1S,3R)-3-(5-(1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate (Intermediate FV)

To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl pyrrolidine-1-carboxylate (200 mg, 624.16 umol, intermediate CK) and 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid (185.2 mg, 567.4 umol, intermediate CI) in ACN (5 mL) was added DIEA (734 mg, 5.67 mmol) and T3P (1.7 g, 2.6 mmol, 50% solution) and the mixture was stirred at 80° C. for 41 h. Upon completion, the reaction mixture was quenched with H ₂ O (5 mL) and extracted with EtOAc (7 mL×2). The combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (200 mg, yield 56%) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.93 (s, 1H), 7.58 (d, J = 2 Hz, 1H), 7.01 (s, 1H), 6.00 (s, 1H), 5.05 - 4.97 (m, 1H), 4.66 (t, J = 5.6 Hz, 2H), 4.12 (d, J = 2.4 Hz, 2H), 3.73 (t, J = 5.6 Hz, 2H), 3.54 - 3.50 (m, 4H), 3.47 - 3.46 (m, 3H), 3.45 (s, 4H), 3.40 (t, J = 2.4 Hz, 1H), 3.22 (br t, J = 6.4 Hz, 5H), 3.07 - 3.01 (m, 1H), 2.39 - 2.32 (m, 1H), 1.90 - 1.84 (m, 1H), 1.81 - 1.69 (m, 8H), 1.51 (s, 9H).

3-(3-Methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FW)

Step 1 - 4-propa-2-ynoxypiperidine-1-carboxylate tert-butyl

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol, CAS#109384-19-2) in anhydrous THF (10 mL) was cooled to 0° C., after which NaH (477 mg, 11.9 mmol, 60% oil dispersion) was added. The reaction mixture was stirred at 0° C. for 0.5 h. 3-Bromoprop-1-yne (1.18 g, 9.94 mmol, 856 uL) was then added. The resulting reaction mixture was stirred at 25° C. for 12 h. Upon completion, the reaction mixture was quenched with water (1 mL) and then diluted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to provide the title compound (2.38 g, 100% yield) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ 4.22 (d, J = 2.4 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.73 - 3.70 (m, 1H), 3.15 - 3.09 (m, 2H), 2.43 (t, J = 2.4 Hz, 1H), 1.93 - 1.82 (m, 2H), 1.61 - 1.50 (m, 2H), 1.47 (s, 9H).

Step 2 - 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate tert-butyl

A suspension of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300 mg, 887 umol, intermediate H), tert-butyl 4-prop-2-ynoxypiperidine-1-carboxylate (318 mg, 1.33 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (124 mg, 177 umol), CuI (33.8 mg, 177 umol), 4A molecular sieves (400 mg) and Cs ₂ CO ₃ (1.16 g, 3.55 mmol) in DMF (5 mL) was degassed under reduced pressure and purged with N ₂ several times, then heated to 80 °C under N ₂ for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with EA (50 mL) and water (20 mL). The organic layer was then separated and washed with brine (5 mL x 2), dried over _{anhydrous Na2SO4} , filtered, and the filtrate was concentrated in vacuo to give a residue which was purified by reverse phase to give the title compound (222 mg, 48% yield) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ 8.09 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.13 (dd, J = 5.2, 12.8 Hz, 1H), 4.39 (s, 2H), 3.76 - 3.66 (m, 6H), 3.09 - 3.03(m, 2H), 2.94 - 2.84 (m, 1H), 2.82 - 2.71 (m, 1H), 2.71 - 2.59 (m, 1H), 2.22 - 2.11 (m, 1H), 1.83 - 1.78 (m, 2H), 1.57 - 1.49 (m, 2H), 1.39 (s, 9H), LC-MS(ESI ⁺ )m/z 441.2(M+H-56) ⁺ .

Step 3 - 3-[3-methyl-2-oxo-4-[3-(4-piperidyloxy)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate (1.50 g, 3.02 mmol) in DCM (30 mL) was added TFA (23.1 g, 202 mmol, 15 mL). The reaction mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (1.50 g, 97% yield, TFA salt) as a yellow oil. LC-MS (ESI+) m/z 397.2 (M+H) ⁺ .

3-(3-Methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FY)

Step 1 - 4-(3-methoxycarbonyl-2-nitro-phenyl)piperazine-1-carboxylate tert-butyl

To a solution of methyl 3-fluoro-2-nitro-benzoate (10.0 g, 50.2 mmol, CAS# 1214353-57-7) and tert-butyl piperazine-1-carboxylate (11.2 g, 60.3 mmol, CAS# 143238-38-4) in ACN (100 mL) was added DIPEA (19.5 g, 151 mmol). The reaction mixture was stirred at 50 °C _for 12 h. Upon completion, the mixture was concentrated in vacuum. The residue was dissolved in water (200 mL) and then extracted with EA (2 x 200 mL). The organic layer was washed with brine (2 x 100 mL), dried over _Na2SO4 , filtered, and the filtrate was concentrated in vacuum to give the title compound (18.3 g, 100% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.86 (dd, J = 1.2, 8.0 Hz, 1H), 7.82 - 7.79 (m, 1H), 7.74 - 7.68 (m, 1H), 3.83 (s, 3H), 3.40 - 3.35 (m, 4H), 2.88 - 2.84 (m, 4H), 1.41 (s, 9H).

Step 2 - 4-(2-amino-3-methoxycarbonyl-phenyl)piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(3-methoxycarbonyl-2-nitro-phenyl)piperazine-1-carboxylate (17.0 g, 46.5 mmol) in THF (15 mL) was added Pd/C (2.00 g, 10 wt%). The reaction mixture was stirred under an atmosphere of H ₂ (15 Psi) at 20° C. for 12 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (15.2 g, 97% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.67 (dd, J = 1.2, 8.0 Hz, 1H), 7.10 (dd, J = 1.2, 7.6 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H), 6.24 (br s, 2H), 4.28 - 3.95 (m, 2H), 3.87 (s, 3H), 3.16 - 2.84 (m, 4H), 2.80 - 2.55 (m, 2H), 1.49 (s, 9H).

Step 3 - 4-[3-Methoxycarbonyl-2-(methylamino)phenyl]piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(2-amino-3-methoxycarbonyl-phenyl)piperazine-1-carboxylate (15.0 g, 44.7 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (40 mL) was added methyl trifluoromethanesulfonate (9.54 g, 58.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Upon completion, the mixture was diluted with water (200 mL) and then extracted with EA (2×200 mL). The organic layer was washed with brine (2×200 mL), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo to give the title compound (15.0 g, 96% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.16 - 7.90 (m, 1H), 7.46 (dd, J = 1.2, 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 3.80 (s, 3H), 3.55 - 3.45 (m, 4H), 2.87 (s, 3H), 2.80 - 2.74 (m, 4H), 1.42 (s, 9H).

Step 4 - 3-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(methylamino)benzoic acid

To a solution of tert-butyl 4-[3-methoxycarbonyl-2-(methylamino)phenyl]piperazine-1-carboxylate (14.0 g, 40.1 mmol) in a mixed solvent of H ₂ O (20 mL) and MeOH (140 mL) was added NaOH (4.81 g, 120 mmol). The reaction mixture was stirred at 70° C. for 12 h. Upon completion, the mixture was concentrated in vacuum. The residue was diluted with water (200 mL) and extracted with EA (100 mL). The organic layer was discarded. The aqueous phase was acidified with HCl (1N) to pH=3-5 and extracted with EA (2×100 mL). The organic layer was washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum. The residue was triturated with MeOH/H ₂ O (1:10, 100 mL) and filtered. The filter cake was dried in vacuo to give the title compound (9.60 g, 71% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 336.1 (M+H) ⁺ .

Step 5 - tert-butyl 4-(3-methyl-2-oxo-1H-benzimidazol-4-yl)piperazine-1-carboxylate

To a solution of 3-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(methylamino)benzoic acid (9.60 g, 28.6 mmol) and DIPEA (11.1 g, 85.9 mmol) in t-BuOH (200 mL) was added DPPA (7.88 g, 28.6 mmol). The reaction mixture was stirred at 85° C. for 12 h. Upon completion, the mixture was concentrated in vacuum. The residue was diluted with water (200 mL) and extracted with EA (2×200 mL). The organic layer was washed with brine (200 mL) and concentrated in vacuum. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (3.35 g, 35% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.84 (s, 1H), 6.94 - 6.87 (m, 1H), 6.85 - 6.79 (m, 1H), 6.75 (dd, J = 1.2, 7.6 Hz, 1H), 4.06 - 3.80 (m, 2H), 3.55 (s, 3H), 3.20 - 2.87 (m, 4H), 2.76 - 2.56 (m, 2H), 1.42 (s, 9H).

Step 6 - tert-butyl 4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl 4-(3-methyl-2-oxo-1H-benzimidazol-4-yl)piperazine-1-carboxylate (3.30 g, 9.93 mmol) in THF (50 mL) was added t-BuOK (1.67 g, 14.9 mmol) at 0° C. After 1 h, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (4.54 g, 11.9 mmol, intermediate G) in THF (20 mL) was added. The reaction mixture was stirred at 0° C. for 3 h. Upon completion, the mixture was acidified with FA to pH=3-5, diluted with water (300 mL), and then extracted with EA (2×300 mL). The organic layer was washed with brine (200 mL) and concentrated in vacuo. The residue was purified by reverse phase flash (0.1% FA) to give the title compound (3.90 g, 70% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 564.3 (M+H) ⁺ .

Step 7 - 3-(3-methyl-2-oxo-4-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate (3.90 g, 6.92 mmol) in TFA (40 mL) was added TfOH (5 mL). The reaction mixture was stirred at 65° C. for 12 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase flash (0.1% FA condition) to give the title compound (1.70 g, 63% yield, FA salt) as a blue solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.06 - 6.99 (m, 1H), 6.96 - 6.92 (m, 2H), 5.36 (dd, J = 5.2, 12.4 Hz, 1H), 3.63 (s, 3H), 3.35 - 3.25 (m, 4H), 3.16 - 2.97 (m, 4H), 2.91 - 2.82 (m, 1H), 2.76 - 2.57 (m, 2H), 2.05 - 1.93 (m, 1H).

1-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperidine-4-carbaldehyde (Intermediate FZ)

Step 1 - 6-chloro-8-cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 4-piperidylmethanol (530 mg, 4.61 mmol, CAS# 6457-49-4) in DCM (20 mL) was added DIEA (2.71 g, 20.9 mmol, 3.65 mL), 4A molecular sieves (2 g) and 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (1.9 g, 4.19 mmol, Intermediate CW). The mixture was stirred at 20 °C for 30 minutes. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-100% ethyl acetate/petroleum ether at 100 mL/min) to give the title compound (2 g, 90% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 532.1 (M+H) ⁺ .

Step 2 - 8-Cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 6-chloro-8-cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 200 umol) in THF (20 mL) was added TEA (57.0 mg, 563 umol) and Pd/C (1 g, 943 umol, 10 wt). The mixture was then stirred at 20° C. under H ₂ atmosphere for 4 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (50 mg, 54% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 498.2 (M+H) ⁺ .

Step 3 - 1-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperidine-4-carbaldehyde

To a solution of 8-cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.00 mmol) in DCE (5 mL) was added DMP (639 mg, 1.51 mmol, 466 uL) at 0° C. The mixture was then stirred at 0-25° C. for 2 h. Upon completion, the reaction mixture was washed with Na ₂ SO ₃ (2 mL×2) at 25° C., then diluted with NaHCO ₃ (2 mL) and extracted with EtOAc (2 mL×2). The combined organic layers were washed with sat. NaCl (2 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0-100% ethyl acetate/petroleum ether at 50 mL/min) to give the title compound as a white solid: LC-MS (ESI ⁺ ) m/z 496.3 (M+H) ⁺ .

3-(3-Methyl-2-oxo-4-(piperazin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate GA)

Step 1 - 4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]piperazine-1-carboxylate tert-butyl

To a solution of 3-[4-(chloromethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (400 mg, 1.30 mmol, Intermediate FH) and tert-butyl piperazine-1-carboxylate (200 mg, 1.07 mmol, CAS# 143238-38-4) in ACN (5.00 mL) was added K ₂ CO ₃ (297 mg, 2.15 mmol). The mixture was stirred at 80° C. for 3 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (430 mg, 87% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.57 (s, 1H), 7.02 - 6.95 (m, 1H), 6.95 - 6.89 (m, 1H), 6.81 - 6.75 (m, 1H), 5.27 (dd, J = 5.2, 12.4 Hz, 1H), 3.80 (s, 3H), 3.75 - 3.67 (m, 2H), 3.47 - 3.35 (m, 4H), 2.99 - 2.90 (m, 1H), 2.90 - 2.80 (m, 1H), 2.80 - 2.68 (m, 1H), 2.55 - 2.35 (m, 4H), 2.29 - 2.17 (m, 1H), 1.46 (s, 9H).

Step 2 - 3-[3-methyl-2-oxo-4-(piperazin-1-ylmethyl)benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]piperazine-1-carboxylate (60.0 mg, 131 umol) in DCM (5.00 mL) was added HCl/dioxane (4 M, 1.00 mL). The reaction mixture was stirred at 20° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (50.0 mg, 96% yield, HCl salt) as a white solid. LC-MS (ESI ⁺ ) m/z 358.1 (M+H) ⁺ .

2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)ethyl 4-methylbenzenesulfonate (Intermediate GB)

Step 1 - 2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)tert-butyl acetate

To a solution of 2-(((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)oxy)tert-butyl acetate (3.50 g, 9.63 mmol, CAS# 27489-63-0) in DMF (40 mL) was added NaH (578 mg, 14.5 mmol, 60% dispersion in mineral oil) at 0 °C under _N2 and the mixture was stirred for 0.5 h. Then _CH3I (2.73 g, 19.3 mmol) was added and the reaction mixture was stirred at 0 °C for 2 h. Upon completion, the reaction was quenched with sat. _NH4Cl (50 mL) _and then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over _Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 9/1) to give the title compound (2.40 g, 66% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.41 - 7.28 (m, 5H), 5.14 (s, 2H), 3.99 (d, J = 1.6 Hz, 2H), 3.33 - 3.23 (m, 1H), 2.79 (s, 3H), 2.14 (d, J = 10.8 Hz, 2H), 1.76 (d, J = 10.4 Hz, 2H), 1.49 (d, J = 1.6 Hz, 13H).

Step 2 - ((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)(methyl)carbamate benzyl

To a solution of 2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)tert-butyl acetate (2.40 g, 6.36 mmol) in THF (30 mL) was added LAH (362 mg, 9.54 mmol) at 0 °C under _N2 and the mixture was stirred at 0 °C for 2 h. Upon completion, the reaction was quenched by addition of _H2O (2.16 mL), filtered and evaporated to give the title compound (1.60 g) as a colorless oil. ^1H NMR (400 MHz, DMSO-d6) δ = 7.37 - 7.34 (m, 3H), 7.33 - 7.32 (m, 1H), 7.27 - 7.19 (m, 1H), 5.15 (t, J = 5.6 Hz, 1H), 5.07 (s, 2H), 4.55 - 4.47 (m, 4H), 3.82 (d, J = 5.2 Hz, 1H), 3.16 - 3.13 (m, 1H), 2.73 (s, 3H), 1.99 (d, J = 2.8 Hz, 2H), 1.78 - 1.73 (m, 2H), 1.56 (d, J = 8.0 Hz, 2H), 1.14 (d, J = 10.8 Hz, 2H).

Step 3 - 4-Methylbenzenesulfonic acid 2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)ethyl

To a solution of ((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)(methyl)carbamate benzyl (1.60 g, 5.21 mmol) in DCM (16 mL) was added TEA (1.05 g, 10.4 mmol), DMAP (159 mg, 1.30 mmol) and TosCl (1.19 g, 6.25 mmol) under _N2 at 0 °C and the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (8 mL x 3), dried _{over Na2SO4} and evaporated. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 4/1) to give the title compound (800 mg, yield 33%) as a yellow oil. ^1H NMR (400 MHz, DMSO-d6) δ = 7.81 - 7.75 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.41 - 7.29 (m, 5H), 5.06 (s, 2H), 4.11 - 4.07 (m, 2H), 3.85 - 3.72 (m, 1H), 3.57 - 3.53 (m, 2H), 3.15 - 3.06 (m, 1H), 2.74 - 2.69 (m, 3H), 2.41 (s, 3H), 1.89 (d, J = 13.2 Hz, 2H), 1.57 - 1.44 (m, 4H), 1.09 (d, J = 12.4 Hz, 2H).

((1r,4r)-4-(2-aminoethoxy)cyclohexyl)(methyl)benzyl carbamate (Intermediate GC)

Step 1 - ((1r,4r)-4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)cyclohexyl)(methyl)carbamate benzyl

A solution of 2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)ethyl 4-methylbenzenesulfonate (800 mg, 2 mmol, Intermediate GB) and potassium 1,3-dioxoisoindolin-2-ide (482 mg, 2.60 mmol) in DMF (8 mL) was stirred at 50° C. for 3 h. Upon completion, the mixture was poured into H ₂ O (5 mL) and filtered. The filter cake was concentrated in vacuo to provide the title compound (680 mg, 90% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.90 - 7.81 (m, 4H), 7.40 - 7.26 (m, 5H), 5.05 (s, 2H), 3.84 - 3.74 (m, 1H), 3.73 - 3.68 (m, 2H), 3.64 - 3.58 (m, 2H), 3.26 - 3.16 (m, 1H), 2.70 (s, 3H), 1.92 (d, J = 12.8 Hz, 2H), 1.58 - 1.47 (m, 4H), 1.12 (dd, J = 5.2, 11.2 Hz, 2H).

Step 2 - ((1r,4r)-4-(2-aminoethoxy)cyclohexyl)(methyl)carbamate benzyl

To a solution of ((1r,4r)-4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)cyclohexyl)(methyl)carbamate benzyl (680 mg, 1.56 mmol) in EtOH (14 mL) was added N ₂ H ₄ .H ₂ O (398 mg, 7.79 mmol). The mixture was stirred at 50° C. for 2 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (470 mg) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 7.43 - 7.28 (m, 5H), 5.07 (s, 2H), 3.88 - 3.77 (m, 1H), 3.47 - 3.41 (m, 2H), 3.19 - 3.13 (m, 1H), 2.73 (s, 3H), 2.67 - 2.62 (m, 2H), 2.05 - 1.97 (m, 2H), 1.56 (d, J = 8.0 Hz, 3H), 1.25 - 1.12 (m, 3H).

4-((8-Cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methyl-N-(2-(((1r,4r)-4-(methylamino)cyclohexyl)oxy)ethyl)benzenesulfonamide (Intermediate GD)

Step 1 - ((1r,4r)-4-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)cyclohexyl)(methyl)carbamate benzyl

To a solution of ((1r,4r)-4-(2-aminoethoxy)cyclohexyl)(methyl)benzylcarbamate (446 mg, 1.46 mmol, Intermediate GC) in DCM (6 mL) was added DIEA (855 mg, 6.62 mmol), 4A molecular sieves (600 mg) and 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (600 mg, 1.32 mmol, Intermediate CW). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 1/2) to afford the title compound (900 mg, 94% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.68 (s, 1H), 8.76 (s, 1H), 8.18 (s, 1H), 7.74 - 7.68 (m, 2H), 7.65 - 7.60 (m, 2H), 7.40 - 7.30 (m, 5H), 5.76 (s, 1H), 5.06 (s, 2H), 3.86 - 3.73 (m, 1H), 3.39 (t, J = 6.0 Hz, 2H), 3.17 - 3.04 (m, 1H), 2.89 (q, J = 6.0 Hz, 2H), 2.70 (s, 3H), 2.33 (s, 3H), 2.14 - 2.09 (m, 2H), 1.97 - 1.92 (m, 2H), 1.76 - 1.64 (m, 5H), 1.56 - 1.46 (m, 5H), 1.13 (d, J = 3.6 Hz, 2H).

Step 2 - 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methyl-N-(2-(((1r,4r)-4-(methylamino)cyclohexyl)oxy)ethyl)benzenesulfonamide

To a solution of ((1r,4r)-4-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)cyclohexyl)(methyl)benzylcarbamate (300 mg, 0.415 mmol) and DIEA (161 mg, 1.24 mmol) in EtOH (3 mL) was added Pd/C (150 mg, 10 wt%) under _N. The suspension was degassed under reduced pressure and purged with _H several times. The mixture was stirred under _H (15 psi) at 25° C. for 2 h. Then, more Pd/C (300 mg, 10 wt%) was added to the mixture, and the mixture was stirred under H ( ₁₅ psi) at 25° C. for 12 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (230 mg) as a yellow oil: LC-MS (ESI ⁺ ) m/z 555.3 (M+H) ⁺ .

tert-Butyl 3-(2-(tosyloxy)ethoxy)azetidine-1-carboxylate (Intermediate GE)

Step 1 - 3-(2-(tert-butoxy)-2-oxoethoxy)azetidine-1-carboxylate tert-butyl

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10 g, 57.7 mmol, CAS#141699-55-0) in DMF (100 mL) was added NaH (2.77 g, 69.2 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred at 25 °C for 1 h, then tert-butyl 2-bromoacetate (16.9 g, 86.6 mmol) was added and the mixture was stirred at 40 °C for 2 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl (100 mL) and extracted with EtOAC (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na ₂ SO ₄ and evaporated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (11 g, 66% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.32 (tt, J = 4.4, 6.4 Hz, 1H), 4.08 (dd, J = 6.4, 10.0 Hz, 2H), 3.94 - 3.89 (m, 4H), 1.47 (s, 9H), 1.43 (s, 9H).

Step 2 - 3-(2-hydroxyethoxy)azetidine-1-carboxylate tert-butyl

To a solution of tert-butyl 3-(2-(tert-butoxy)-2-oxoethoxy)azetidine-1-carboxylate (8.8 g, 31 mmol) in THF (90 mL) was added LAH (1.74 g, 45.9 mmol) at 0° C. and the mixture was stirred at 0° C. for 2 h. Upon completion, the mixture was quenched with H ₂ O (1.8 mL) and 15% aqueous NaOH (1.8 mL), additional H ₂ O (6 mL) and the mixture was stirred at 0° C. for 10 min. The mixture was then filtered and the filtrate was concentrated to give the title compound (4.4 g) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 4.27 - 4.16 (m, 1H), 4.16 - 3.94 (m, 4H), 3.83 - 3.74 (m, 2H), 3.71 - 3.64 (m, 4H), 3.58 - 3.51 (m, 3H), 3.41 (td, J = 4.4, 9.2 Hz, 5H), 3.00 - 2.88 (m, 2H), 2.29 (s, 3H), 1.37 (s, 9H).

Step 3 - 3-(2-(tosyloxy)ethoxy)azetidine-1-carboxylate tert-butyl

To a solution of tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (4.4 g, 20.3 mmol) in DCM (80 mL) and THF (20 mL) was added TEA (4.10 g, 40.5 mmol), DMAP (618 mg, 5.06 mmol) and 4-methylbenzenesulfonyl chloride (5.79 g, 30.4 mmol), then the mixture was stirred at ₂₅ °C for 12 h. Upon completion, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried over _Na2SO4 and concentrated in reduced pressure. The residue was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 48%-78%, 15 min) to give the title compound (2.1 g, 28% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.85 - 7.79 (m, 2H), 7.39 - 7.34 (m, 3H), 4.21 - 4.15 (m, 3H), 4.05 - 3.98 (m, 2H), 3.76 - 3.70 (m, 2H), 3.62 - 3.56 (m, 2H), 2.47 (s, 4H), 1.45 (s, 10H).

3-(5-(1-(2-(azetidin-3-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate GF)

Step 1 - 3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)ethoxy)azetidine-1-carboxylate tert-butyl

To a solution of tert-butyl 3-(2-(tosyloxy)ethoxy)azetidine-1-carboxylate (250 mg, 673 umol, intermediate GE) in DMF (2 mL) was added 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (192 mg, 560 umol, intermediate DB from SMA) and DIEA (217.5 mg, 1.68 mmol, 293.08 uL), then the mixture was stirred at 60° C. for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl (5 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (7 mL×3), dried over Na ₂ SO ₄ and evaporated. The crude product was purified by reverse phase HPLC (0.1% FA) to give the title compound (40 mg, 13% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 542.3 (M+H) ⁺ .

Step 2 - 3-(5-(1-(2-(azetidin-3-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)ethoxy)azetidine-1-carboxylate (40 mg, 73.9 umol) in DCM (2 mL) was added TFA (0.4 mL) and the mixture was then stirred at 25° C. for 4 h. Upon completion, the mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (60 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 442.2 (M+H) ⁺ .

(Intermediate GG)

((1r,4r)-4-(2-(prop-2-yn-1-yloxy)ethoxy)cyclohexyl)carbamate tert-Butyl (Intermediate GH)

Step 1 - 2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)ethyl acetate

To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (12 g, 56 mmol, CAS#111300-06-2) in DCM (100 mL) was added diacetoxyrhodium (1.23 g, 5.57 mmol) and ethyl 2-diazoacetate (47.7 g, 334 mmol) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 5 h. Upon completion, the reaction was poured into water (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (2×80 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (11 g, 65% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 4.43 - 4.31 (m, 1H), 3.74 - 3.68 (m, 2H), 3.59 - 3.54 (m, 2H), 3.51 - 3.37 (m, 1H), 3.27 (qt, J = 3.6, 10.8 Hz, 1H), 2.02 (br s, 4H), 1.44 (s, 9H), 1.41 - 1.33 (m, 2H), 1.21 - 1.11 (m, 2H).

Step 2 - ((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)carbamate tert-butyl

To a solution of ethyl 2-[4-(tert-butoxycarbonylamino)cyclohexoxy]acetate (11 g, 37 mmol) in THF (110 mL) and MeOH (22 mL) was added LiBH ₄ (2.87 g, 131 mmol) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 2 h. Upon completion, the reaction was quenched with saturated aqueous citric acid (120 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers are washed with brine (60 mL×2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (6.5 g, 69% yield) as a yellow gum. ^1H NMR (400 MHz, _CDCl3 ) δ = 4.46 - 4.27 (m, 1H), 3.73 - 3.67 (m, 2H), 3.61 - 3.53 (m, 2H), 3.50 - 3.37 (m, 1H), 3.33 - 3.19 (m, 1H), 2.04 (br dd, J = 2.1, 10.5 Hz, 4H), 1.50 - 1.42 (m, 9H), 1.41 - 1.33 (m, 2H), 1.21 - 1.08 (m, 2H).

Step 3 - ((1r,4r)-4-(2-(prop-2-yn-1-yloxy)ethoxy)cyclohexyl)carbamate tert-butyl

To a solution of tert-butyl N-[4-(2-hydroxyethoxy)cyclohexyl]carbamate (0.4 g, 2 mmol) in THF (10 mL) was added NaH (123 mg, 3.08 mmol, 60% dispersion in mineral oil) and 3-bromoprop-1-yne (366 mg, 3.08 mmol) at 0° C. under nitrogen flow. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase was washed with brine (2×10 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (450 mg, 98% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 4.48 - 4.28 (m, 1H), 4.21 (d, J = 2.4 Hz, 2H), 3.73 - 3.58 (m, 4H), 3.51 - 3.35 (m, 1H), 3.25 (tt, J = 3.6, 10.4 Hz, 1H), 2.42 (t, J = 2.4 Hz, 1H), 2.08 - 1.96 (m, 4H), 1.49 - 1.41 (m, 8H), 1.40 - 1.32 (m, 2H), 1.20 - 1.05 (m, 2H).

3-(5-((Z)-4-(2-(((1r,4r)-4-aminocyclohexyl)oxy)ethoxy)-2-chlorobut-1-en-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate GI)

Step 1 - ((1r,4r)-4-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)cyclohexyl)carbamate tert-butyl

To a solution of tert-butyl N-[4-(2-prop-2-ynoxyethoxy)cyclohexyl]carbamate (0.45 g, 1.51 mmol, intermediate GH) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (562 mg, 1.66 mmol, intermediate J) in THF (4.5 mL) and ACN (4.5 mL) was added Cs ₂ CO ₃ (2.47 g, 7.57 mmol) and XPhos Pd G3 (384 mg, 453 umol) at 20° C. under nitrogen flow. The reaction was then stirred at 60° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was poured into water (10 mL) and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (10 mL x 2) and dried over sodium sulfate. Then it was filtered to obtain a filtrate and concentrated to obtain a residue. The residue was purified by column chromatography on silica gel eluting with (petroleum ether:ethyl acetate=100:1 to 100:80). The title compound (550 mg, yield 65.5%) was obtained as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.11 (dd, J = 1.2, 8.2 Hz, 1H), 7.04 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.13 (dd, J = 5.2, 12.8 Hz, 1H), 4.42 - 4.25 (m, 3H), 3.70 - 3.64 (m, 2H), 3.63 - 3.57 (m, 2H), 3.35 (s, 4H), 3.19 (tt, J = 3.6, 10.4 Hz, 1H), 2.92 - 2.80 (m, 1H), 2.22 - 2.11 (m, 1H), 2.00 - 1.85 (m, 4H), 1.62 - 1.49 (m, 2H), 1.40 - 1.34 (m, 9H), 1.33 - 1.26 (m, 2H), 1.11 - 0.97 (m, 2H).

Step 2 - 3-(5-((Z)-4-(2-(((1r,4r)-4-aminocyclohexyl)oxy)ethoxy)-2-chlorobut-1-en-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A solution of tert-butyl N-[4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]cyclohexyl]carbamate (400 mg, 721 umol) in HCl/dioxane (4 M, 5 mL) under nitrogen flow at 0° C. The reaction was then stirred at 20° C. under nitrogen atmosphere for 2 hours. Upon completion, the reaction was concentrated to give the title compound (400 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 491.2 (M+H) ⁺ .

2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethanamine (Intermediate GJ)

Step 1 - (1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexanol

To a solution of 4-(hydroxymethyl)cyclohexanol (10 g, 76.8 mmol, CAS#3685-27-6) and imidazole (5.75 g, 84.5 mmol) in DMF (300 mL) was added TBDPSCl (22.1 g, 80.6 mmol) at 0° C., then the mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was quenched with water (300 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (300 mL×3) and dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (19 g, 67% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.71 - 7.63 (m, 4H), 7.48 - 7.35 (m, 6H), 3.56 (tt, J = 4.4, 10.8 Hz, 1H), 3.47 (d, J = 6.4 Hz, 2H), 2.05 - 1.96 (m, 2H), 1.90 - 1.79 (m, 2H), 1.33 - 1.20 (m, 3H), 1.06 (m, 11H).

Step 2 - 2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethyl acetate

To a solution of (1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexanol (10 g, 30 mmol) and Rh ₂ (OAc) ₄ (1.20 g, 2.71 mmol) in DCM (100 mL) was added ethyl 2-diazoacetate (18.5 g, 162 mmol) dropwise at 0° C., then the mixture was stirred at 25° C. under N ₂ atmosphere for 12 h. Upon completion, the mixture was quenched with HOAc (50 mL) and H ₂ O (100 mL), then extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL×3) and dried over Na ₂ SO ₄ and concentrated in vacuum and purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (8 g, yield 65%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.71 - 7.61 (m, 4H), 7.44 - 7.34 (m, 6H), 4.31 - 4.23 (m, 1H), 4.23 (br d, J = 7.2 Hz, 2H), 4.12 (s, 2H), 3.46 (d, J = 6.1 Hz, 2H), 3.35 - 3.21 (m, 1H), 2.18 - 2.02 (m, 2H), 1.92 - 1.79 (m, 2H), 1.05 (s, 9H).

Step 3 - 2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethanol

To a solution of ethyl 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]acetate (6 g, 10 mmol) in THF (60 mL) and MeOH (12 mL) was added LiBH ₄ (862 mg, 39.5 mmol) at 0° C. The mixture was stirred at 0-20° C. for 2 h. Upon completion, the reaction mixture was quenched by addition of saturated aqueous citric acid (120 mL) at 0° C., then diluted with EtOAc (120 mL) and extracted with EtOAc (120 mL×3). The combined organic layers were washed with brine (120 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1-1/1) to give the title compound (5 g, 92% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 413.1 (M+H) ⁺ .

Step 4 - 4-Methylbenzenesulfonic acid 2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethyl

To a solution of 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethanol (5 g, 12.1 mmol) in DCM (80 mL) and THF (20 mL) was added TEA (2.45 g, 24.2 mmol), DMAP (370 mg, 3.03 mmol), and TosCl (3.47 g, 18.1 mmol). The mixture was stirred at 25 °C for 12 h. Upon completion, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (4 g, 58% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.82 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 1.2, 7.6 Hz, 4H), 7.47 - 7.31 (m, 8H), 4.22 - 4.13 (m, 2H), 3.69 - 3.64 (m, 2H), 3.46 (d, J = 6.0 Hz, 2H), 3.22 - 3.08 (m, 1H), 2.45 (s, 3H), 1.96 (br d, J = 9.6 Hz, 2H), 1.87 - 1.77 (m, 2H), 1.48 (dt, J = 2.4, 6.0 Hz, 1H), 1.27 (t, J = 7.2 Hz, 1H), 1.21 - 1.10 (m, 2H), 1.06 (s, 9H), 1.02 - 0.85 (m, 3H).

Step 5 - 2-(2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethyl)isoindoline-1,3-dione

To a solution of 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl 4-methylbenzenesulfonate (2 g, 3.53 mmol) in DMF (10 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (980 mg, 5.29 mmol) and the mixture was then stirred at 50° C. for 4 h. Upon completion, the mixture was quenched with water (10 mL) and filtered. The filter cake was washed with water (10 mL×3) to give the title compound (2 g) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.88 (dd, J = 3.2, 5.2 Hz, 2H), 7.74 (dd, J = 3.2, 5.2 Hz, 2H), 7.66 (dd, J = 1.6, 7.6 Hz, 4H), 7.48 - 7.32 (m, 6H), 3.95 - 3.86 (m, 2H), 3.79 - 3.69 (m, 2H), 3.45 (d, J = 6.4 Hz, 2H), 3.28 - 3.18 (m, 1H), 2.05 - 1.95 (m, 2H), 1.88 - 1.79 (m, 2H), 1.56 - 1.45 (m, 1H), 1.26 - 1.13 (m, 2H), 1.10 - 0.91 (m, 11H).

Step 6 - 2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethanamine

To a solution of 2-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]isoindoline-1,3-dione (2 g, 3.69 mmol) in EtOH (80 mL) was added NH ₂ NH ₂ .H ₂ O (1.63 g, 27.6 mmol, 85% solution) and the mixture was stirred at 50° C. for 2 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (1.2 g) as a yellow gum. LC-MS (ESI ⁺ ) m/z 442.3 (M+K) ⁺ .

4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-(2-(((1r,4r)-4-formylcyclohexyl)oxy)ethyl)-3-methylbenzenesulfonamide (Intermediate GK)

Step 1 - N-(2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethyl)-4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide

To a solution of 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (500 mg, 1.10 mmol, Intermediate CW) and 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethanamine (681 mg, 1.65 mmol, Intermediate GJ) in DCM (10 mL) was added DIEA (712 mg, 5.51 mmol) and 4A molecular sieves (500 mg), then the mixture was stirred at 25° C. for 30 minutes. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (900 mg) as a yellow oil. LC-MS (ESI ⁺ ) m/z 828.3 (M+H) ⁺ .

Step 2 - 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-(2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)ethyl)-3-methylbenzenesulfonamide

A solution of N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide (900 mg, 1.09 mmol) in TBAF (2 M, 10 mL) was stirred for 1 h at 25° C. Upon completion, the mixture was concentrated in vacuo and purified by reverse phase HPLC (0.1% FA condition) to afford the title compound (250 mg, 39% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.57 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.79 - 7.74 (m, 3H), 7.42 (br s, 1H), 5.92 (quin, J = 8.8 Hz, 1H), 4.85 (t, J = 6.0 Hz, 1H), 3.54 (t, J = 5.2 Hz, 2H), 3.46 (d, J = 6.4 Hz, 2H), 3.18 - 3.09 (m, 3H), 2.45 (s, 3H), 2.36 - 2.25 (m, 2H), 2.13 - 1.98 (m, 5H), 1.96 - 1.78 (m, 5H), 1.75 - 1.66 (m, 3H), 1.50 - 1.40 (m, 2H), 1.25 - 1.10 (m, 3H), 1.04 - 0.90 (m, 2H).

Step 3 - 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-(2-(((1r,4r)-4-formylcyclohexyl)oxy)ethyl)-3-methylbenzenesulfonamide

To a solution of 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-N-[2-[4-(hydroxymethyl)cyclohexoxy]ethyl]-3-methyl-benzenesulfonamide (200 mg, 338 umol) in DCM (4 mL) was added DMP (215 mg, 508 umol), and the mixture was then stirred at 25° C. for 12 h. Upon completion, the mixture was quenched with sat. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL×3), the combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo to give the title compound (250 mg) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 9.64 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.27 (dd, J = 1.6, 7.6 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.94 (ddd, J = 1.6, 7.2, 8.4 Hz, 1H), 7.78 - 7.74 (m, 4H), 7.32 (s, 1H), 5.93 (quin, J = 8.8 Hz, 1H), 4.83 (t, J = 6.0 Hz, 1H), 3.54 (t, J = 5.2 Hz, 2H), 3.20 - 3.10 (m, 3H), 2.45 (s, 3H), 2.38 - 2.28 (m, 2H), 2.09 - 1.98 (m, 7H), 1.96 - 1.85 (m, 3H), 1.76 - 1.65 (m, 3H), 1.42 - 1.22 (m, 5H).

3-[4-[4-[azetidin-3-ylmethyl(methyl)amino]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GL)

Step 1 - 3-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]azetidine-1-carboxylate tert-butyl

To a mixture of 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg, 245 umol, HCl, intermediate EG) in a mixed solvent of THF (2 mL) and DMF (0.5 mL), DIEA (63.3 mg, 490 umol) was added at −15° C. until pH=8. The mixture was then stirred at −15° C. for 10 min, and HOAc (44.1 mg, 735 umol) was added at −15° C. until pH=6. The mixture was then stirred at −15° C. for 20 min. Then tert-butyl 3-formylazetidine-1-carboxylate (47.6 mg, 257 umol, CAS#177947-96-5) was added and the mixture was stirred at −15° C. for 1 hour. Finally, NaBH(OAc) ₃ (103 mg, 490 umol) was added. The resulting reaction mixture was stirred at −15° C. for 1 hour. Upon completion, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100×30 mm×5 um; mobile phase: [water (FA)-ACN]; B%: 3%-33%, 8 min) to give the title compound (60 mg, 45% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 6.99 - 6.84 (m, 3H), 5.38 - 5.28 (m, 1H), 3.88 (s, 2H), 3.63 (s, 3H), 3.46 (d, J = 5.2 Hz, 2H), 3.14 (d, J = 11.2 Hz, 2H), 2.89 (s, 1H), 2.71 - 2.67 (m, 2H), 2.63 (s, 2H), 2.19 (s, 3H), 2.02 - 1.96 (m, 1H), 1.82 - 1.74 (m, 2H), 1.71 - 1.59 (m, 2H), 1.37 (s, 9H), 1.36 (d, J = 1.2 Hz, 4H). LCMS(ESI ⁺ ) m/z 541.2(M+H) ⁺ .

Step 2 - 3-[4-[4-[azetidin-3-ylmethyl(methyl)amino]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 3-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]azetidine-1-carboxylate (40.0 mg, 73.9 umol) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to give the title compound (40.0 mg, 97% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 441.1 (M+H) ⁺ .

tert-Butyl N-(3-oxopropyl)carbamate (Intermediate GM)

To a solution of tert-butyl N-(3-hydroxypropyl)carbamate (500 mg, 2.85 mmol, CAS#58885-58-8) in DCM (6 mL) was added DMP (1.45 g, 3.42 mmol). The mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with Na ₂ S ₂ O _{3.5H 2} O (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give the title compound (300 mg, yield 60%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 9.82 (s, 1H), 4.91 (d, J = 0.8 Hz, 1H), 3.43 (q, J = 5.6 Hz, 2H), 2.72 (t, J = 5.6 Hz, 2H), 1.44 (s, 9H).

3-[4-[4-[3-aminopropyl(methyl)amino]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GN)

Step 1 - N-[3-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]propyl]carbamic acid tert-butyl 3109

To a solution of 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg, 269 umol, HCl salt, Intermediate EG) and tert-butyl N-(3-oxopropyl)carbamate (60.6 mg, 350 umol, Intermediate GM) in a mixture of THF (2 mL) and DMF (0.5 mL) was added KOAc (264 mg, 2.69 mmol) and NaBH(OAc) ₃ (114 mg, 538 umol). The mixture was stirred at 0° C. for 1 h. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) at 0° C. and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 9 min) to give the title compound (75.0 mg, 52% yield) as a white solid. LCMS (ESI ⁺ ) m/z 529.5 (M+H) ⁺ .

Step 2 - 3-[4-[4-[3-aminopropyl(methyl)amino]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[3-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]propyl]carbamate (75.0 mg, 141 umol) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (75.0 mg, 97% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 429.0 (M+H) ⁺ .

1-[8-[4-(methylamino)-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione (Intermediate GO)

Step 1 - 4-bromo-8-chloro-isoquinoline

A mixture of 8-chloroisoquinoline (5.00 g, 30.5 mmol, CAS#34784-07-1), NBS (7.07 g, 39.7 mmol) in HOAc ( ₅₀ mL) was degassed and purged with N 3 times, then the mixture was stirred at 50 °C under N ₂ atmosphere for 40 min. Upon completion, the reaction mixture was neutralized with 15% NaOH (20 mL) and the mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (50 mL) and dried over anhydrous Na ₂ SO _4. Filtration and concentration in reduced pressure gave a residue. The residue was then purified by column chromatography to give the title compound (400 mg, 73.90% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 -d) δ 9.58 (s, 1H), 8.79 (s, 1H), 8.12 - 8.05 (m, 1H), 7.73 - 7.66 (m, 2H).

Step 2 - 1-(8-chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione

To a solution of 4-bromo-8-chloro-isoquinoline (200 mg, 824 umol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (231 mg, 989 umol, intermediate CS) in DMF (3 mL) was added CuI (47.1 mg, 247 umol), K ₂ CO ₃ (227 mg, 1.65 mmol) and 2-aminoacetic acid (18.5 mg, 247 umol). The mixture was then purged with N ₂ three times and stirred at 140 °C for 8 h. Upon completion, the mixture was filtered, diluted with water (100 mL) and extracted with EA (5 × 80 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give a residue. The residue was then purified by reverse-phase HPLC (0.1% FA) to give the title compound (99.2 mg, 30.41% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.56 (s, 1H), 8.72 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.83 - 7.77 (m, 1H), 7.29 - 7.23 (m, 2H), 6.91 - 6.84 (m, 2H), 4.84 (s, 2H), 4.01- 3.94 (m, 1H), 3.80 - 3.75 (m, 1H), 3.73 - 3.71 (m, 3H), 3.20 - 3.12 (m, 1H), 3.01 - 2.93 (m, 1H). LC-MS(ESI ⁺ )m/z 396.0(M+H) ⁺ .

Step 3 - N-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-8-isoquinolyl]-4-piperidyl]-N-methyl-tert-butyl carbamate

To a solution of 1-(8-chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (200 mg, 505 umol) and tert-butyl N-methyl-N-(4-piperidyl)carbamate (119 mg, 555 umol, CAS#108612-54-0) in dioxane (4 mL) was added Cs ₂ CO ₃ (329 mg, 1.01 mmol) and Pd-PEPPSI-IHept ^Cl 3-chloropyridine (49.1 mg, 50.5 umol), then the mixture was stirred for 8 h at 80° C. Upon completion, the mixture was filtered, diluted with water (20 mL) and extracted with EA (4×10 mL). The extract was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (216 mg, 74.52% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.45 (s, 1H), 8.53 (s, 1H), 7.72 - 7.66 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.31 - 7.24 (m, 3H), 6.88 (d, J = 8.8 Hz, 2H), 4.83 (s, 2H), 3.93 - 3.87 (m, 1H), 3.78 - 3.71 (m, 4H), 3.50 - 3.42 (m, 2H), 3.17 - 3.08 (m, 1H), 2.99 - 2.96 (m, 1H), 2.81 (s, 3H), 2.18 - 2.03 (m, 2H), 1.75 - 1.68 (m, 2H), 1.43 (s, 9H), 0.88 - 0.70 (m, 3H); LC-MS(ESI ⁺ )m/z 574.3(M+H) ⁺ .

Step 4 - 1-[8-[4-(methylamino)-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl N-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-8-isoquinolyl]-4-piperidyl]-N-methyl-carbamate (206 mg, 359 umol) in TFA (0.5 mL) and TfOH (0.05 mL) was stirred at 70° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (100 mg, 78.80% yield, TFA) as a yellow solid. LC-MS (ESI ⁺ ) m/z 354.0 (M+H) ⁺ .

Step 5 - N-[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolyl]-4-piperidyl]-N-methyl-tert-butyl carbamate

To a solution of 1-[8-[4-(methylamino)-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione (100 mg, 282 umol) in DCM (1 mL) was added Et ₃ N (787 uL, 5.66 mmol) and Boc ₂ O (92.6 mg, 424 umol) at 0° C., then the mixture was stirred for 13 h at 25° C. Upon completion, the mixture was concentrated in vacuo to give a residue, which was then purified by reverse phase (0.1% FA condition) to give the title compound (70.0 mg, 54.55% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.53 (s, 1H), 9.45 (s, 1H), 8.53 (s, 1H), 7.75 - 7.68 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 4.15 - 3.96 (m, 1H), 3.92 - 3.86 (m, 1H), 3.72 - 3.66 (m, 1H), 3.48 - 3.41 (m, 2H), 3.01 - 2.84 (m, 3H), 2.81 (s, 3H), 2.78 - 2.71 (m, 1H), 2.19 - 2.02 (m, 2H), 1.72 - 1.70 (m, 2H), 1.43 (s, 9H). LC-MS(ESI ⁺ )m/z 454.1(M+H) ⁺ .

Step 6 - 1-[8-[4-(methylamino)-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolyl]-4-piperidyl]-N-methyl-carbamate (60 mg, 132 umol) in DCM (1 mL) was added TFA (0.5 mL, 6.75 mmol) and the mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (58.0 mg, 93.79% yield, TFA) as a yellow solid. LC-MS (ESI ⁺ ) m/z 354.0 (M+H) ⁺ .

1-[8-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione (Intermediate GP)

Step 1 - 4-[[[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolyl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of 1-[8-[4-(methylamino)-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione (100 mg, 213 umol, TFA, intermediate GO) in THF (1 mL) was added TEA (29.8 uL, 214 umol). 4-Formylpiperidine-1-carboxylate tert-butyl (41.0 mg, 192 umol, CAS# 137076-22-3) and HOAc (12.2 uL, 214 umol) were then added and the mixture was stirred at -10°C for 0.5 hours. NaBH(OAc) ₃ (68.0 mg, 321 umol) was then added and the mixture was stirred at -10°C for 1.5 hours. Upon completion, the mixture was quenched with water (1 mL) and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 15 min) to give the title compound (70.0 mg, 59% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.53 (s, 1H), 9.43 (s, 1H), 8.53 (s, 1H), 7.75 - 7.68 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 4.00 - 3.85 (m, 3H), 3.72 - 3.66 (m, 1H), 3.50 - 3.43 (m, 2H), 3.00 - 2.92 (m, 2H), 2.88 - 2.65 (m, 6H), 2.53 - 2.51 (m, 4H), 2.05 - 1.87 (m, 4H), 1.75 - 1.72 (m, 3H), 1.40 (s, 9H), 1.11 - 0.94 (m, 2H). LC-MS(ESI ⁺ )m/z 551.4(M+H) ⁺ .

Step 2 - 1-[8-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl 4-[[[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolyl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate (35.0 mg, 63.5 umol) in DCM (0.5 mL) was added HCl/dioxane (3M, 0.5 mL) and the mixture was then stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (30.0 mg, 97% yield, HCl) as a yellow solid. LC-MS (ESI ⁺ ) m/z 451.2 (M+H) ⁺ .

1-[8-[4-(methylamino)-1-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (Intermediate GQ)

Step 1 - N-[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]imidazo[1,2-a]pyridin-8-yl]-4-piperidyl]-N-methyl-tert-butyl carbamate

A solution of 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (600 mg, 1.40 mmol, synthesized by steps 1-2 of intermediate BN), tert-butyl N-methyl-N-(4-piperidyl)carbamate (449 mg, 2.10 mmol), _Cs2CO3 (1.37 g, 4.19 mmol), PD-PEPPSI- _IHeptCl3 -chloropyridine (67.9 mg, 69.8 umol ₎ and 4A molecular sieves (50 mg) in dioxane (15 mL) was stirred at 100 °C under _N2 for 16 h. Upon completion, the reaction mixture was diluted with EtOAc (40 mL) and washed with water (30 mL x 3). The organic layer was dried _{over Na2SO4} and concentrated in vacuo. The residue was triturated with water (20 mL) at 25°C for 10 min to give the title compound (780 mg, 99% yield) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.78 (d, J = 6.4 Hz, 1H), 7.47 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.84 - 6.79 (m, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.81 (s, 2H), 4.11 - 3.92 (m, 1H), 3.83 - 3.75 (m, 2H), 3.72 (s, 3H), 2.93-3.06 (m, 2H), 2.78 - 2.66 (m, 7H), 1.90 - 1.81 (m, 2H), 1.65 (d, J = 9.6 Hz, 2H), 1.41 (s, 9H).

Step 2 - 1-[8-[4-(methylamino)-1-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl N-[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]imidazo[1,2-a]pyridin-8-yl]-4-piperidyl]-N-methyl-carbamate (200 mg, 355 umol) and TfOH (680 mg, 4.53 mmol) in TFA (2 mL) was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (162 mg, 99% yield, TFA) as a red oil. LC-MS (ESI ⁺ ) m/z 343.2 (M+H) ⁺ .

1-[8-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (intermediate GR)

Step 1 - 4-[[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-8-yl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of 1-[8-[4-(methylamino)-1-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (162 mg, 354 umol, TFA, Intermediate GQ), TEA (71.8 mg, 709 umol), HOAc (63.9 mg, 1.06 mmol) in DMF (1 mL) and THF (1.5 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (113 mg, 532 umol) and the mixture was stirred at 25° C. for 0.5 h. Then NaBH(OAc) ₃ (150 mg, 709 umol) was added to the mixture and stirred at 25° C. for 1 h. Upon completion, the reaction was quenched with water (0.2 mL) and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (143 mg, 74% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.75 (s, 1H), 8.93 - 8.74 (m, 1H), 8.32 - 8.00 (m, 1H), 7.98 - 7.60 (m, 1H), 7.12 - 6.90 (m, 1H), 4.31 - 4.07 (m, 1H), 4.00 - 3.92 (m, 2H), 3.85 - 3.75 (m, 2H), 3.51 - 3.46 (s, 2H), 3.22 - 3.12 (m, 1H), 3.00 - 2.92 (m, 1H), 2.88 - 2.69 (m, 9H), 2.19 - 2.06 (m, 2H), 2.00 - 1.80 (m, 4H), 1.68 (d, J = 11.6 Hz, 1H), 1.40 (s, 9H), 1.19 - 1.05 (m, 2H).

Step 2 - 1-[8-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione

A mixture of tert-butyl 4-[[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-8-yl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate (76.0 mg, 140 umol) in HCl/EtOAc (2 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (67 mg, 99% yield, HCl) as a yellow solid. LC-MS (ESI ⁺ ) m/z 440.3 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[4-[2-(4-piperidyl)ethyl]piperazin-1-yl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GS)

Step 1 - 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate tert-butyl

To a solution of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate H) and tert-butyl piperazine-1-carboxylate (550 mg, 2.96 mmol) in dioxane (10 mL) was added 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (254 mg, 295 umol, CAS#1435347-24-2) and _Cs2CO3 ( ₉₆₃ mg, 2.96 mmol). The mixture was stirred at 100°C under _N2 atmosphere for 16 hours. Upon completion, the reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (200 mg, 28% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 444.2 (M+H) ⁺ .

Step 2 - 3-[3-methyl-2-oxo-4-[4-[2-(4-piperidyl)ethyl]piperazin-1-yl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (80.0 mg, 144 umol) in DCM (1 mL) was added TFA (16.5 mg, 144 umol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (70 mg, 86% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 344.0 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[4-[2-(4-piperidyl)ethyl]piperazin-1-yl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GT)

Step 1 - 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate tert-butyl

To a solution of 3-(3-methyl-2-oxo-4-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione (77.0 mg, 224 umol, intermediate GS) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (56.1 mg, 246 umol, CAS#142374-19-4) in THF (1 mL) and DMF (0.2 mL) was added KOAc (220 mg, 2.24 mmol). The mixture was stirred at 0° C. for 6 min. NaBH(OAc) ₃ (95.1 mg, 448 umol) was then added and the mixture was stirred at 0° C. for 1 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 13%-43%, 10 min) to give the title compound (80 mg, 64% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 555.3 (M+H) ⁺ .

Step 2 - 3-[3-methyl-2-oxo-4-[4-[2-(4-piperidyl)ethyl]piperazin-1-yl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (80.0 mg, 144 umol) in DCM (1 mL) was added TFA (16.4 mg, 144 umol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (70 mg, 85% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 455.4 (M+H) ⁺ .

4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide (Intermediate GU)

Step 1 - 4-[3-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (50.0 mg, 205 umol, CAS# 373608-48-1) in a mixture of ACN (2 mL) and DMSO (0.5 mL) was added DIEA (53.1 mg, 410 umol) and 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (139 mg, 308 umol, Intermediate CW). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by prep-HPLC (column: Waters xbridge 150×25 mm 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 46%-76%, 8 min) to give the title compound (130 mg, 95% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.68 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.53 (t, J = 5.6 Hz, 1H), 5.78 - 5.67 (m, 1H), 3.27 - 3.19 (m, 4H), 2.78 (q, J = 6.4 Hz, 2H), 2.33 (s, 3H), 2.25 - 2.21 (m, 2H), 2.21 - 2.16 (m, 4H), 2.15 - 2.06 (m, 2H), 1.69 (s, 4H), 1.56 - 1.48 (m, 2H), 1.46 (s, 2H), 1.36 (s, 9H). LCMS(ESI ⁺ )m/z 660.1(M+H) ⁺ .

Step 2 - 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide

To a solution of tert-butyl 4-[3-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylate (80.0 mg, 121 umol) in DCM (1.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound (80.0 mg, 97% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 560.2 (M+H) ⁺ .

3-(3-Methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione (Intermediate GV)

Step 1 - 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carboxylate tert-butyl

A mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, intermediate J), tert-butyl piperazine-1-carboxylate (1.32 g, 5.91 mmol, CAS#57260-71-6), 4A molecular sieves, RuPhos (275 mg, 591 umol), and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (459 mg, 591 umol) in toluene (10 mL) was degassed and purged with _N three times, then the mixture was stirred at 25 °C under _N atmosphere for 30 min. LiHMDS (1 M, 10.3 mL) was then added slowly to the mixture. The mixture was then stirred at 80° C. under _N2 atmosphere for 2 h. Upon completion, the mixture was diluted with DMF (25 mL) and adjusted to pH=5 with FA, then filtered with DCM and concentrated in vacuo. The crude product was triturated with PE:EA=1:1 (10 mL) at 25° C. for 30 min, then filtered to give the title compound (820 mg, 57% yield). ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.07 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 2.0, 8.4 Hz, 1H), 5.30 (dd, J = 5.2, 12.8 Hz, 1H), 3.50 - 3.47 (m, 4H), 3.31 (s, 3H), 3.06 - 3.02 (m, 4H), 2.90 (s, 1H), 2.63 (s, 1H), 2.53 (d, J = 2.0 Hz, 2H), 1.43 (s, 9H). LC-MS(ESI ⁺ )m/z 444.1(M+H) ⁺ .

Step 2 - 3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carboxylate (100 mg, 225 umol) in DCM (1 mL) was added HCl/dioxane (4M, 1 mL). The mixture was then stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to give the desired product (76 mg, 88% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 343.9 (M+H) ⁺ .

3-[5-[4-[[4-(2-aminoethoxy)cyclohexyl]methyl]piperazin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GW)

Step 1 - N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]methyl]cyclohexoxy]ethyl]carbamate tert-butyl

To a solution of 3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione (50 mg, 131 umol, HCl, Intermediate GV) and tert-butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate (35.7 mg, 131 umol, Intermediate DP) in THF (0.5 mL) and DMF (0.5 mL) was added KOAc (129 mg, 1.32 mmol) and NaBH(OAc) ₃ (55.8 mg, 263 umol). The mixture was then stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The crude product was then purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 7%-37%, 9 min) to give the title compound (65 mg, 82% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 599.3 (M+H) ⁺ .

Step 2 - 3-[5-[4-[[4-(2-aminoethoxy)cyclohexyl]methyl]piperazin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]methyl]cyclohexoxy]ethyl]carbamate (55.0 mg, 91.8 umol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was then stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (45.0 mg, 79% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 499.1 (M+H) ⁺ .

3-[5-(azetidin-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GX)

Step 1 - 3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]azetidine-1-carboxylate tert-butyl

To a solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate J), tert-butyl 3-bromoazetidine-1-carboxylate (453 mg, 1.92 mmol, CAS# 1064194-10-0) in DME (2 mL) was added Ir[dF( _CF3 )ppy] ₂ (dtbpy)( _PF6 ) (16.5 mg, 14.7 umol), TTMSS (367 mg, 1.48 mmol), 2,6-lutidine (316 mg, 2.96 mmol) and _NiCl2.dtbbpy (22 umol). The reaction was stirred and irradiated with a purple 10 W LED lamp (3 cm away) for 14 h using cooling water to maintain the reaction temperature at 25° C. Upon completion, the reaction mixture was purified by prep-HPLC (Column: YMC Triart C18 250×50 mm×7 um; Mobile phase: [Water (FA)-ACN]; B%: 25%-55%, 20 min) to afford the title compound (600 mg, 97% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.21 (d, J = 1.2 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.99 (dd, J = 1.2, 8.0 Hz, 1H), 5.36 (dd, J = 5.2, 12.8 Hz, 1H), 4.29 - 4.23 (m, 2H), 3.86 (s, 2H), 3.84 - 3.78 (m, 1H), 3.36 (s, 3H), 2.96 - 2.85 (m, 1H), 2.78 - 2.71 (m, 1H), 2.67 - 2.62 (m, 1H), 2.04 - 1.97 (m, 1H), 1.41 (s, 9H). LC-MS(ESI ⁺ )m/z 359.6(M+H) ⁺ .

Step 2 - 3-[5-(azetidin-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]azetidine-1-carboxylate (100 mg, 241 umol) in DCM (1 mL) was added HCl/dioxane (4M, 1 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the desired product (84 mg, 99% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 314.9 (M+H) ⁺ .

3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]azetidin-3-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GY)

Step 1 - N-[2-[4-[[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]azetidin-1-yl]methyl]cyclohexoxy]ethyl]carbamate tert-butyl

To a solution of 3-[5-(azetidin-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (55 mg, 156.umol, HCl, Intermediate GX), tert-butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate (50 mg, 184 umol, Intermediate DP) in DMF (0.5 mL) and THF (0.5 mL) was added KOAc (180 mg, 1.84 mmol) and NaBH(OAc) ₃ (78.1 mg, 368 umol). The mixture was then stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The crude was then purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 7%-37%, 9 min) to give the title compound (55 mg, 52% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 570.3 (M+H) ⁺ .

Step 2 - 3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]azetidin-3-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]azetidin-1-yl]methyl]cyclohexoxy]ethyl]carbamate (55.0 mg, 96.5 umol) in DCM (0.5 mL) was added TFA (651 mg, 5.71 mmol). The mixture was then stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (50.0 mg, 89% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 470.1 (M+H) ⁺ .

3-[3-Methyl-4-[3-(methylamino)azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GZ)

Step 1 - N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]azetidin-3-yl]-N-methyl-benzyl carbamate

A mixture of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate H), N-(azetidin-3-yl)-N-methyl-benzylcarbamate (651 mg, 2.96 mmol), DABCO (165 mg, 1.48 mmol, 162 uL), NiBr2.glyme ( ₃₂₄ mg, 1.05 mmol) and Ir(ppy) ₂ (dtbbpy) _PF6 (1.35 g, 1.48 mmol) in DMA (15 mL) was degassed three times. The reaction vial was then sealed with parafilm, placed 2 cm away from one blue LED and irradiated at 25° C. for 14 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1), (Rf=0.50, PE:EA=1:1) to give the title compound (620 mg, yield 87%) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.08 (d, J = 6.0 Hz, 1H), 7.42 - 7.26 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.14 - 6.90 (m, 3H), 6.76 - 6.75(m, 1H), 5.44 - 5.26 (m, 1H), 5.09 (s, 1H), 4.02 (t, J = 6.8 Hz, 1H), 3.86 (d, J = 6.0 Hz, 1H), 3.66 - 3.52 (m, 2H), 3.34 (s, 3H), 2.99 (s, 2H), 2.94 (s, 3H), 2.74 - 2.68 (m, 2H), 2.68 - 2.62 (m, 2H). LC-MS(ESI ⁺ )m/z 477.9(M+H) ⁺ .

Step 2 - 3-[3-methyl-4-[3-(methylamino)azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]azetidin-3-yl]-N-methyl-benzylcarbamate (200 mg, 418 umol), Pd/C (20.0 mg, 4.19 umol, 10 wt%) in THF (1.5 mL) was degassed and purged with _H2 three times. The mixture was then stirred at 25° C. under _H2 atmosphere for 1 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (140 mg, 97% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 343.8 (M+H) ⁺ .

3-[3-Methyl-4-[3-[methyl(4-piperidylmethyl)amino]azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HA)

Step 1 - 4-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]azetidin-3-yl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of 3-[3-methyl-4-[3-(methylamino)azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (140 mg, 407 umol, intermediate GZ) and tert-butyl 4-formylpiperidine-1-carboxylate (86.9 mg, 407 umol, CAS# 137076-22-3) in the mixed solvent DMF (1 mL) and THF (1 mL) was added KOAc (400 mg, 4.08 mmol). The mixture was stirred at 0° C. for 6 minutes. Then, NaBH(OAc) ₃ (172 mg, 815 umol) was added to the above solution. The mixture was stirred at 0° C. for 2.4 hours. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) and then concentrated in vacuum. The mixture was purified by pre-HPLC (column: Phenomenex C18 150×25 mm×10 um; mobile phase: [water (NH4HCO3)-CAN]; B%: 33%-63%, 8 min) to give the title compound (22 mg, 10% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 541.2 (M+H) ⁺ .

Step 2 - 3-[3-methyl-4-[3-[methyl(4-piperidylmethyl)amino]azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]azetidin-3-yl]-methyl-amino]methyl]piperidine-1-carboxylate (22.0 mg, 40.6 umol) in DCM (2 mL) and TFA (2 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (17.0 mg, 75% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 441.0 (M+H) ⁺ .

7'-Cyclopentyl-2'-methylsulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (Intermediate HB)

Step 1 - 2-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]ethyl acetate

To a solution of ethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)acetate (1.00 g, 4.05 mmol, CAS#61727-34-2) in dioxane (10 mL) was added cyclopentanamine (690 mg, 8.11 mmol, CAS#1003-03-8) and TEA (820 mg, 8.11 mmol). The mixture was stirred at 60 °C for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 °C and then extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1.10 g, 91% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.81 (s, 1H), 5.73 (d, J = 6.0 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.31 (s, 2H), 2.51 (s, 3H), 2.12 - 2.03 (m, 2H), 1.78 - 1.71 (m, 2H), 1.68 - 1.61 (m, 2H), 1.53 - 1.44 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H). LC-MS(ESI ⁺ ) m/z 296(M+H) ⁺ .

Step 2 - 7-Cyclopentyl-2-methylsulfanyl-5H-pyrrolo[2,3-d]pyrimidin-6-one

To a solution of ethyl 2-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]acetate (1.00 g, 3.39 mmol) in THF (10 mL) was added t-BuOK (1.14 g, 10.1 mmol). The mixture was stirred at 35° C. for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25° C. and then extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (800 mg, 94% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 250.0 (M+H) ⁺ .

Step 3 - 7'-Cyclopentyl-2'-methylsulfanyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one

To a suspension of NaH (5.01 g, 125 mmol, 60% dispersion in mineral oil) in THF (5 mL) was added dropwise a solution of N-[bis(dimethylamino)phosphoryl]-N-methylmethanamine (11.2 g, 62.5 mmol) in 1,2-dibromoethane (11.7 g, 62.5 mmol, CAS#106-93-4) in THF (5 mL) and the reaction mixture was stirred at 0° C. for 30 min. Then, 7-cyclopentyl-2-methylsulfanyl-5-H-pyrrolo[2,3-d]pyrimidin-6-one (7.80 g, 31.2 mmol) was added and the reaction mixture was heated to 50° C. for 1 h. Upon completion, the reaction mixture was quenched with 1M HCl aq. (10 mL) at 25° C. and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (7.5 g, 87% yield) as a pink oil. LC-MS (ESI ⁺ ) m/z 276.0 (M+1) ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 7.77 (s, 1H), 4.89 - 4.80 (m, 1H), 2.57 (s, 3H), 2.29 - 2.20 (m, 2H), 2.02 - 1.89 (m, 4H), 1.79 (q, J = 4.4 Hz, 2H), 1.71 - 1.63 (m, 2H), 1.58 (q, J = 4.0 Hz, 2H).

Step 4 - 7'-Cyclopentyl-2'-methylsulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one

To a solution of 7'-cyclopentyl-2'-methylsulfanyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (5.15 g, 18.7 mmol) in DCM (50 mL) was added m-CPBA (11.3 g, 56.1 mmol, 85%). The mixture was stirred at 40°C for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (30 mL) at 25°C and then extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 0/1) to give the title compound (3.00 g, 52% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.05 (s, 1H), 4.96 - 488 (m, 1H), 3.34 (s, 3H), 2.23 - 2.16 (m, 2H), 2.05 - 2.00 (m, 2H), 2.00 - 1.95 (m, 4H), 1.82 - 1.78 (m, 2H), 1.72 - 1.67 (m, 2H). LC-MS(ESI ⁺ ) m/z 307.7(M+1) ⁺ .

4-[(7'-cyclopentyl-6'-oxo-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate HC)

Step 1 - 2'-(4-benzylsulfanyl-2-methyl-anilino)-7'-cyclopentyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one

A mixture of 7'-cyclopentyl-2'-methylsulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (1.00 g, 3.25 mmol, Intermediate HB), 4-benzylsulfanyl-2-methyl-aniline (895 mg, 3.90 mmol, Intermediate DE), _4A molecular sieves (3.25 mmol), _Cs2CO3 (3.18 g, 9.76 mmol), Pd(OAc) ₂ (73.0 mg, 325 umol) and BINAP (405 mg, 650 umol) in toluene (10 mL) was degassed and purged with _N2 three times. This mixture was then stirred at 100 °C under _N2 atmosphere for 12 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was then purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 55%-85%, 17 min) to give the title compound (300 mg, 20% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 457.2 (M+1) ⁺ .

Step 2 - 4-[(7'-cyclopentyl-6'-oxo-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-2'-yl)amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2'-(4-benzylsulfanyl-2-methyl-anilino)-7'-cyclopentyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (85.0 mg, 186 umol) in H ₂ O (0.12 mL), ACN (2 mL) and AcOH (0.2 mL) was added NCS (74.5 mg, 558 umol). The mixture was stirred at 25°C for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25°C and then extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 1/1) to give the title compound (80 mg, 99% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 433.0 (M+1) ⁺ .

tert-Butyl N-[4-(2-oxoethoxy)cyclohexyl]carbamate (Intermediate HD)

To a solution of tert-butyl N-[4-(2-hydroxyethoxy)cyclohexyl]carbamate (500 mg, 1.93 mmol, synthesized by steps 1-2 of intermediate GH) in DCM (5 mL) was added DMP (1.23 g, 2.89 mmol, 895 uL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was quenched with Na ₂ S ₂ O ₃ (20 mL), extracted with DCM (20 mL×3), washed with NaHCO ₃ (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1-2/1) (Rf=0.50, PE:EA=1:1) to give the title compound (490 mg, 98% yield) as a brown oily liquid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.56 (s, 1H), 6.70 (s, 1H), 4.15 (s, 1H), 4.12 - 3.98 (m, 1H), 3.54 - 3.38 (m, 2H), 1.98 - 1.87 (m, 2H), 1.75 (d, J = 10.0 Hz, 2H), 1.37 (s, 9H), 1.17 (dd, J = 6.0, 12.8 Hz, 4H).

3-[5-[1-[2-(4-aminocyclohexoxy)ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HE)

Step 1 - N-[4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethoxy]cyclohexyl]carbamate tert-butyl

To a solution of tert-butyl N-[4-(2-oxoethoxy)cyclohexyl]carbamate (150 mg, 582 umol, Intermediate HD) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (186 mg, 408 umol, TFA, Intermediate DB) in a mixture of DMF (1 mL) and THF (1 mL) was added KOAc (572 mg, 5.83 mmol). The mixture was stirred at 0° C. for 6 minutes. Then, NaBH(OAc) ₃ (247 mg, 1.17 mmol) was added to the above solution. The mixture was then stirred at 0° C. for 2.4 hours. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) and then concentrated in vacuo. The mixture was purified by pre-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 11%-41%, 9 min) to give the title compound (80.0 mg, 23% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 584.2 (M+H) ⁺ .

Step 2 - 3-[5-[1-[2-(4-aminocyclohexoxy)ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethoxy]cyclohexyl]carbamate (100 mg, 171 umol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (20.0 mg, 19% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 484.1 (M+H) ⁺ .

1-[7-(4-piperidyl)-4-isoquinolyl]hexahydropyrimidine-2,4-dione (intermediate HF)

Step 1 - 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl

To a solution of 1-(7-chloroisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 378 umol, synthesized by steps 1-2 of intermediate BM) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (140 mg, 454 umol, CAS# 286961-14-6) in dioxane (2.0 mL) and water (0.2 mL) was added Xphos Pd G ₍ 29.8 mg, 37.8 umol) and K _PO (160 mg, 757 umol). The mixture was then stirred at 80° C. _for 6 hours. Upon completion, the reaction solution was diluted with water (20 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC to give the title compound (170 mg, 67% yield) as a brown oil. LC-MS (ESI ⁺ ) m/z 543.4 (M+H) ⁺ .

Step 2 - 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-7-yl)piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (160 mg, 294 umol) in THF (20 mL) was added Pd/C (30 mg, 294 umol, 10 wt%) under _N2 . The mixture was stirred at 20 °C under a _H2 balloon (15 psi) for 1 h. Upon completion, the mixture was filtered through Celite and then washed with THF (50 mL). The filtrate was concentrated in vacuo to afford the title compound (130 mg, 72% yield) as a brown oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.26 (s, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 1.6, 8.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.90 - 6.86 (m, 2H), 4.83 (s, 2H), 4.13 (d, J = 11.0 Hz, 2H), 3.94 - 3.91 (m, 1H), 3.73 (s, 3H), 3.66 - 3.54 (m, 4H), 3.15 - 3.08 (m, 1H), 3.02 - 2.97 (m, 1H), 1.88 - 1.85 (m, 2H), 1.68 - 1.57 (m, 2H), 1.35 (s, 9H); LC-MS(ESI ⁺ )m/z 545.2(M+H) ⁺ .

Step 3 - 1-(7-(piperidin-4-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

A solution of tert-butyl 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-7-yl)piperidine-1-carboxylate (40.0 mg, 73.4 umol) in TFA (1.0 mL) and TfOH (0.05 mL) was stirred at 70° C. for 3 h. Upon completion, the residue was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 mm x 25 mm x 10 um; mobile phase: [water (0.225% FA)-MeCN]; B%: 1%-15%, 11.5 min), then further purified by Prep-HPLC (column: Waters xbridge, 150 mm x 25 mm x 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-MeCN]; B%: 0%-26%, 11 min) to give the title compound (1.03 mg, 4% yield) as a white solid. ^1H NMR (DMSO- _d6 , 400 Hz) δ 10.53 (s, 1H), 9.26 (s, 1H), 8.48 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.77 - 7.74 (m, 1H), 3.96 - 3.89 (m, 1H), 3.75 - 3.69 (m, 1H), 3.09 (d, J = 12.0 Hz, 2H), 3.00 - 2.72 (m, 4H), 2.65 - 2.62 (m, 2H), 1.80 (d, J = 12 Hz, 2H), 1.68 - 1.58 (m, 2H); LC-MS(ESI ⁺ )m/z 325.0(M+H) ⁺ .

1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione (Intermediate HG)

Step 1 - tert-butyl N-[2-[4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-7-isoquinolyl]-1-piperidyl]methyl]cyclohexoxy]ethyl]carbamate

To a solution of 1-[7-(4-piperidyl)-4-isoquinolyl]hexahydropyrimidine-2,4-dione (134 mg, 305 umol, TFA, Intermediate HF), TEA (30.9 mg, 305 umol) and HOAc (36.7 mg, 611 umol) in DMF (1 mL) and THF (1 mL) was added tert-butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate (82.9 mg, 305 umol, Intermediate DP) at −10° C. The mixture was stirred at −10° C. for 0.5 h. To the above mixture was then added NaBH(OAc) ₃ (97.1 mg, 458 umol) at −10° C. and the mixture was stirred at −10° C. for 1 h. Upon completion, the mixture was quenched with H ₂ O (0.05 mL). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 15 min) to give the title compound (100 mg, 56% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 9.24 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.83 - 7.78 (m, 1H), 7.76 - 7.71 (m, 1H), 4.88 (t, J = 4.8 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.89 - 3.74 (m, 4H), 3.52 (t, J = 5.2 Hz, 2H), 3.29 (d, J = 5.2 Hz, 2H), 3.25 - 3.11 (m, 2H), 3.07 - 2.89 (m, 7H), 2.87 - 2.70 (m, 3H), 2.63 - 2.41 (m, 3H), 2.16 - 2.03 (m, 5H), 1.97 (d, J = 13.2 Hz, 2H), 1.89 - 1.78 (m, 1H), 1.30 - 1.09 (m, 5H).

Step 2 - 1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl N-[2-[4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-7-isoquinolyl]-1-piperidyl]methyl]cyclohexoxy]ethyl]carbamate (100 mg, 172 umol) in HCl/EtOAc (3 mL) was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (89 mg, 99% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 480.1 (M+H) ⁺ .

1-[7-(4-piperidyl)imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (intermediate HH)

Step 1 - 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate tert-butyl

To a 40 mL vial equipped with a stir bar was added 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (498 mg, 1.61 mmol, Intermediate AZ), tert-butyl 4-bromopiperidine-1-carboxylate (553 mg, 2.10 mmol, CAS# 180695-79-8), Ir[dF(CF3)ppy] ₂ (dtbpy)( _PF6 ) (36.1 mg, 32.2 umol), NiCl2.dtbbpy ( _19.2 mg, 48.3 umol), TTMSS (400 mg, 1.61 mmol) and 2,6-dimethylpyridine (345 mg, 3.22 mmol) in DME (50 mL). The reaction was stirred and irradiated with 4 x 50 W [455 nm] blue LED lamps (3 cm apart) for 14 h, using cooling water to maintain the reaction temperature at 25° C. Upon completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo. The crude product was purified by reverse phase (0.1% FA condition) to give the title compound (220 mg, 33% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.65 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 6.98 - 6.91 (m, 1H), 4.16 - 4.02 (m, 2H), 3.78 (t, J = 6.8 Hz, 2H), 2.87 - 2.73 (m, 5H), 1.82 (d, J = 12.8 Hz, 2H), 1.54 (m, J = 4.4, 12.4 Hz, 2H), 1.42 (s, 9H).

Step 2 - 1-[7-(4-piperidyl)imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (220 mg, 532 umol) in HCl/EtOAc (4 mL) was stirred for 1 h at 25° C. Upon completion, the mixture was concentrated in vacuo to afford the title compound (186 mg, 99% yield, HCl) as a white solid. LCMS (ESI ⁺ ) m/z 314.0 (M+H) ⁺ .

1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (Intermediate HI)

Step 1 - tert-butyl N-[2-[4-[[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]-1-piperidyl]methyl]cyclohexoxy]ethyl]carbamate

To a solution of 1-[7-(4-piperidyl)imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (103 mg, 294 umol, HCl, Intermediate HH), TEA (29.8 mg, 294 umol) and HOAc (35.4 mg, 589 umol) in DMF (1 mL) and THF (1 mL) was added tert-butyl N-[2-(4-formylcyclohexoxy)ethyl]carbamate (80 mg, 294 umol, Intermediate DP) at −10° C. The mixture was stirred at −10° C. for 0.5 h. Then, NaBH(OAc) ₃ (93.7 mg, 442 umol) was added to the above mixture at −10° C. and the mixture was stirred at −10° C. for 1 h. Upon completion, the mixture was quenched with H ₂ O (0.05 mL). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 1%-30%, 15 min) to give the title compound (70 mg, 41% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.40 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 6.91 (dd, J = 1.2, 7.2 Hz, 1H), 5.38 - 4.84 (m, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.58 - 3.48 (m, 4H), 3.28 (d, J = 5.2 Hz, 2H), 3.24 - 3.15 (m, 1H), 2.98 - 2.90 (m, 2H), 2.82 - 2.68 (m, 3H), 2.62 - 2.52 (m, 2H), 2.37 - 2.24 (m, 2H), 2.08 (d, J = 10.4 Hz, 2H), 1.95 (d, J = 13.2 Hz, 4H), 1.74 (m, 1H), 1.45 (s, 9H), 1.28 - 1.18 (m, 2H), 1.14 - 1.03 (m, 2H).

Step 2 - 1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl N-[2-[4-[[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]-1-piperidyl]methyl]cyclohexoxy]ethyl]carbamate (70.0 mg, 123 umol) in HCl/EtOAc (3 mL) was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to provide the title compound (60 mg, 96% yield, HCl) as a white solid. LCMS (ESI ⁺ ) m/z 469.4 (M+H) ⁺ .

tert-Butyl 6-(3-oxopropoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate HJ)

Step 1 - 6-allyloxy-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.00 g, 4.69 mmol, CAS#1147557-97-8) in DMF (20 mL) was added NaH (375 mg, 9.38 mmol, 60% purity) and 3-bromoprop-1-ene (850 mg, 7.03 mmol, CAS#106-95-6). The mixture was then stirred at 0° C. for 3 h. Upon completion, the reaction mixture was washed with brine (100 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 5/1) to give the title compound (1.08 g, 90% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 5.99 - 5.84 (m, 1H), 5.31 - 5.25 (m, 1H), 5.21 - 5.17 (m, 1H), 3.91 (s, 2H), 3.90 - 3.87 (m, 5H), 2.52 - 2.46 (m, 2H), 2.17 - 2.10 (m, 2H), 1.45 (s, 9H).

Step 2 - 6-(3-hydroxypropoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-allyloxy-2-azaspiro[3.3]heptane-2-carboxylate (1.08 g, 4.26 mmol) in THF (12 mL) was added 9-BBN (0.5 M, 25.58 mL) at 0 °C. The mixture was then stirred at 25 °C for 16 h. The reaction solution was cooled to 0 °C, then deionized water (1 mL) and NaOH (3 M, 6 mL) were added. Then, H ₂ O ₂ (4.77 g, 39.2 mmol, 28% solution) was added at 0 °C, and the mixture was stirred for 30 min. Upon completion, the mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (800 mg, 69% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.89 (s, 2H), 3.86 (s, 2H), 3.84 - 3.77 (m, 3H), 3.75 (t, J = 5.6 Hz, 2H), 3.49 (t, J = 6.0 Hz, 2H), 2.51 - 2.42 (m, 2H), 2.11 - 2.03 (m, 2H), 1.42 (s, 9H).

Step 3 - 6-(3-oxopropoxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-(3-hydroxypropoxy)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 737 umol) in DCM (4 mL) was added DMP (375 mg, 884 umol). The mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with Na ₂ S ₂ O _{3.5H 2} O (10 mL) and then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (90 mg, 45% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 9.79 (s, 1H), 4.35 (t, J = 5.2 Hz, 2H), 3.90 (s, 2H), 3.87 (s, 3H), 3.65 (t, J = 6.0 Hz, 2H), 2.68 - 2.62 (m, 2H), 2.47 (d, J = 6.4 Hz, 2H), 1.44 (s, 9H).

3-[5-[1-[3-(2-azaspiro[3.3]heptan-6-yloxy)propyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HK)

Step 1 - 6-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propoxy]-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (60.0 mg, 131 umol, TFA salt, Intermediate DB) and tert-butyl 6-(3-oxopropoxy)-2-azaspiro[3.3]heptane-2-carboxylate (35.4 mg, 131 umol, Intermediate HJ) in a mixture of THF (2 mL) and DMF (0.5 mL) was added KOAc (129 mg, 1.31 mmol) and NaBH(OAc) ₃ (55.7 mg, 262 umol). The mixture was stirred at 0° C. for 1 h. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) at 0° C. and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 9 min) to give the title compound (50 mg, 63% yield) as a white solid. LCMS (ESI ⁺ ) m/z 596.5 (M+H) ⁺ .

Step 2 - 3-[5-[1-[3-(2-azaspiro[3.3]heptan-6-yloxy)propyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 6-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propoxy]-2-azaspiro[3.3]heptane-2-carboxylate (50.0 mg, 83.9 umol) in DCM (1 mL) was added TFA (2.31 g, 20.2 mmol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (50.0 mg, 97% yield, TFA salt) as a white solid. LCMS (ESI ⁺ ) m/z 496.2 (M+H) ⁺ .

N-[2-(4-piperidyloxy)ethyl]benzylcarbamate (Intermediate HL)

Step 1 - 4-[2-(tert-butoxycarbonylamino)ethoxy]piperidine-1-carboxylate benzyl

To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (400 mg, 1.70 mmol, CAS# 95798-23-5) in DMF (8 mL) was added NaH (136 mg, 3.40 mmol, 60% dispersion in mineral oil) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then benzyl 2,2-dioxooxathiazolidine-3-carboxylate (437 mg, 1.70 mmol, CAS# 1215021-54-7) was added. The reaction mixture was stirred at 25 °C for 15.5 h. The reaction mixture was washed with brine (30 mL) and extracted with DCM (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 5/1) to give the title compound (300 mg, 46% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 - 7.20 (m, 5H), 5.04 (s, 2H), 3.69 - 3.65 (m, 2H), 3.46 (s, 2H), 3.16 - 3.08 (m, 2H), 2.97 - 2.95 (m, 2H), 2.90 - 2.80 (m, 1H), 1.64 - 1.56 (m, 2H), 1.43 (d, J = 4.4 Hz, 2H), 1.39 (s, 9H). LCMS(ESI ⁺ )m/z 401.1(M+Na) ⁺ .

Step 2 - N-[2-(4-piperidyloxy)ethyl]benzyl carbamate

To a solution of tert-butyl 4-[2-(benzyloxycarbonylamino)ethoxy]piperidine-1-carboxylate (110 mg, 290 umol) in DCM (1.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound (110 mg, 96% yield, TFA) as a colorless oil. LCMS (ESI ⁺ ) m/z 279.2 (M+H) ⁺ .

3-[5-[4-[[4-(2-aminoethoxy)-1-piperidyl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HM)

Step 1 - N-[2-[[1-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-4-piperidyl]oxy]ethyl]benzyl carbamate

To a solution of benzyl N-[2-(4-piperidyloxy)ethyl]carbamate (110 mg, 280 umol, TFA, Intermediate HL) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (103 mg, 280 umol, Intermediate DM) in a mixture of THF (2 mL) and DMF (0.5 mL) was added KOAc (275 mg, 2.80 mmol) and NaBH(OAc) ₃ (118 mg, 560 umol). The mixture was stirred at 0° C. for 1 h. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) at 0° C. and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 0%-30%, 9 min) to give the title compound (60.0 mg, 33% yield) as a white solid. LCMS (ESI ⁺ ) m/z 633.5 (M+H) ⁺ .

Step 2 - 3-[5-[4-[[4-(2-aminoethoxy)-1-piperidyl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of benzyl N-[2-[[1-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-4-piperidyl]oxy]ethyl]carbamate (60.0 mg, 94.8 umol) in THF (3 mL) was added Pd/C (40.0 mg, 94.8 umol, 10 wt%) under _N2 . The suspension was degassed in vacuum and purged with _H2 several times. The mixture was stirred at 25°C under _H2 (20 psi) for 1 h. Upon completion, the reaction was filtered and the filtrate was concentrated in vacuum to give the title compound (30 mg, 63% yield) as a white solid. LCMS (ESI ⁺ ) m/z 499.2 (M+H) ⁺ .

8-Cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate HN)

Step 1 - 5-bromo-2-chloro-N-cyclopentyl-pyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloro-pyrimidine (5.00 g, 21.9 mmol, CAS#36082-50-5) in dioxane (100 mL) was added cyclopentanamine (2.24 g, 26.3 mmol, CAS#1003-03-8). The mixture was stirred at 25° C. for 6 h. Upon completion, the reaction mixture was extracted with H ₂ O (100 mL) at 25° C. and then with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 1/1) to give the title compound (7.50 g, 61% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.22 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 4.35 - 4.26 (m, 1H), 1.92 - 1.88 (m, 2H), 1.72 - 1.65 (m, 2H), 1.63 - 1.51 (m, 4H).

Step 2 - 5-Bromo-N-cyclopentyl-2-methylsulfanyl-pyrimidin-4-amine

A solution of 5-bromo-2-chloro-N-cyclopentyl-pyrimidin-4-amine (2.00 g, 7.23 mmol) in DMF (20 mL) was degassed and purged with _N2 three times, then NaSMe (1.29 g, 18.4 mmol) was added to the mixture. The mixture was stirred at 25 °C under _{N2 atmosphere for 16 h. Upon completion, the reaction mixture was quenched with H2O (20 mL) at 25 °C and then extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4 , filtered} , and concentrated in vacuo to give a residue. The crude product was then purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (2.00 g, 95% yield) as an off-white oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.05 (s, 1H), 5.27 (d, J = 4.0 Hz, 1H), 4.44 - 4.36 (m, 1H), 2.50 (s, 3H), 2.15 - 2.07 (m, 2H), 1.78 - 1.63 (m, 4H), 1.53 - 1.45 (m, 2H).

Step 3 - (E)-3-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoic acid methyl ester

A mixture of 5-bromo-N-cyclopentyl-2-methylsulfanyl-pyrimidin-4-amine (2.00 g, 6.94 mmol), TEA (2.11 g, 20.8 mmol), Pd(PPh ₃ ) ₄ (801 mg, 693 umol) in DMF (20 mL) was degassed and purged with N ₂ three times. Methyl prop-2-enoate (3.11 g, 36.1 mmol, CAS#96-33-3) was then added to the mixture, and the mixture was then stirred at 90 °C under N ₂ atmosphere for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 °C and then extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The crude product was then purified by reverse-phase HPLC (0.1% FA) to give the title compound (1.37 g, 67% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.14 (s, 1H), 7.49 (d, J = 16.0 Hz, 1H), 6.27 (dd, J = 1.2, 15.6 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.52 - 4.44 (m, 1H), 3.83 - 3.79 (m, 3H), 2.58 - 2.51 (m, 3H), 2.19 - 2.08 (m, 2H), 1.81 - 1.62 (m, 4H), 1.53 - 1.45 (m, 2H).

Step 4 - 8-Cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of methyl (E)-3-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop- _{2-enoate (1.00 g, 3.41 mmol) in NMP (10 mL) was added DBU (2.59 g, 17.0 mmol). The mixture was stirred at 120° C. for 1 h. Upon completion, the reaction mixture was quenched with H 2} O (20 mL) at 25° C. and then extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (484 mg, 54% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 262.0 (M+1) ⁺ .

4-[[8-Cyclopentyl-6-(difluoromethyl)-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate HO)

Step 1 - 6-[chloro(difluoro)methyl]-8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a 40 mL vial equipped with a stir bar was added 8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 3.83 mmol, Intermediate HN), 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) (2.09 g, 8.60 mmol, CAS# 2834-23-3), 1-oxido-4-phenyl-pyridin-1-ium (1.31 g, 7.65 mmol), and Ru(bpy _{) 3Cl2.6H2O} ( _28.6 mg, 38.2 umol) in dry ACN (10 mL). The vial was sealed and placed under nitrogen and added. The reaction was stirred and irradiated with 4×50 W [455 nm] blue LED lamps (3 cm apart) for 14 h, using cooling water to maintain the reaction temperature at 25° C. Upon completion, the mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column; mobile phase: [water (TFA)-ACN]; B%: 35%-85%, 30 min) to give the title compound (1.10 g, 83% yield) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.04 (s, 1H), 8.51 (s, 1H), 5.87 (q, J = 8.8 Hz, 1H), 2.61 (s, 3H), 2.27 - 2.17 (m, 2H), 2.03 - 1.97 (m, 2H), 1.89 - 1.82 (m, 2H), 1.70 - 1.61 (m, 2H). LC-MS(ESI ⁺ ) m/z 346.0(M+H) ⁺ .

Step 2 - 8-Cyclopentyl-6-(difluoromethyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-[chloro(difluoro)methyl]-8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (1.10 g, 3.18 mmol) in MeOH (12 mL) was added Na ₂ CO ₃ (505 mg, 4.77 mmol) and Pd/C (600 mg, 3.18 mmol, 10 wt %). The mixture was stirred at 25° C. under H ₂ (15 psi) for 4 h. Upon completion, the mixture was filtered and concentrated in vacuo to afford the title compound (990 mg, 99% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.02 (d, J = 6.0 Hz, 1H), 8.37 - 8.27 (m, 1H), 5.90 - 5.81 (m, 1H), 4.12 (s, 1H), 2.61 - 2.60 (m, 3H), 2.24 - 2.19 (m, 2H), 2.01 - 1.97 (m, 2H), 1.86 - 1.81 (m, 2H), 1.67 - 1.62 (m, 2H). LC-MS(ESI ⁺ ) m/z 311.9(M+H) ⁺ .

Step 3 - 8-Cyclopentyl-6-(difluoromethyl)-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-6-(difluoromethyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (990 mg, 3.18 mmol) in DCM (10 mL) was added m-CPBA (968 mg, 4.77 mmol, 85% solution) at 0° C. The mixture was then stirred at 25° C. for 8 h. Upon completion, the mixture was quenched with Na ₂ S ₂ O ₃ 5H ₂ O (50 mL), washed with NaHCO ₃ solution (3×50 mL) and extracted with DCM (3×50 mL). The organic layer was then washed with brine (3×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , PE/EA=62/38) to give the title compound (500 mg, 4% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.41 (d, J = 4.8 Hz, 1H), 8.58 - 8.46 (m, 1H), 7.20 - 6.87 (m, 1H), 5.87 - 5.76 (m, 1H), 3.48 - 3.45 (m, 3H), 2.25 - 2.16 (m, 2H), 2.12 - 2.05 (m, 2H), 1.93 - 1.84 (m, 2H), 1.70 - 1.62 (m, 2H). LC-MS(ESI ⁺ ) m/z 344.0(M+H) ⁺ .

Step 4 - 2-(4-benzylsulfanyl-2-methyl-anilino)-8-cyclopentyl-6-(difluoromethyl)pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-6-(difluoromethyl)-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (500 mg, 1.46 mmol) and 4-benzylsulfanyl-2-methyl-aniline (667 mg, 2.91 mmol, intermediate DE) in i-PrOH (5 mL) was added TFA (1.66 g, 14.56 mmol). The mixture was stirred at 85° C. for 6 h. Upon completion, the mixture was cooled to room temperature, diluted with H ₂ O (30 mL) and extracted with EA (3×30 mL). The combined organic phase was washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , PE/EA=63/37) to give the title compound (195 mg, 27% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.63 - 9.58 (s, 1H), 8.82 (s, 1H), 8.11 (s, 1H), 7.40 - 7.35 (m, 2H), 7.33 - 7.25 (m, 5H), 7.22 - 7.19 (m, 1H), 7.02 - 6.74 (m, 1H), 5.78 - 5.48 (m, 1H), 4.24 (s, 2H), 2.17 (s, 3H), 2.11 - 2.03 (m, 2H), 1.65 - 1.36 (m, 6H). LC-MS(ESI ⁺ )m/z 493.1(M+H) ⁺ .

Step 5 - 4-[[8-cyclopentyl-6-(difluoromethyl)-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-8-cyclopentyl-6-(difluoromethyl)pyrido[2,3-d]pyrimidin-7-one (195 mg, 395 umol) in a mixed solvent of ACN (2 mL), AcOH (200 uL) and H ₂ O (20 uL) was added NCS (158 mg, 1.19 mmol). The mixture was stirred at 25° C. in dark for 0.5 h. Upon completion, the mixture was diluted with H ₂ O (5 mL) and extracted with EA (3×10 mL). The organic layer was washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the liquid was concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , PE/EA=85/15) to give the title compound (165 mg, 88% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.61 (s, 1H), 8.83 (s, 1H), 8.12 (s, 1H), 7.49 (s, 1H), 7.46 - 7.40 (m, 1H), 7.38 - 7.32 (m, 1H), 7.04 - 6.74 (m, 1H), 5.74 - 5.60 (m, 1H), 2.22 (s, 3H), 2.16 - 2.07 (m, 2H), 1.74 - 1.60 (m, 4H), 1.46 - 1.39 (m, 2H). LC-MS(ESI ⁺ )m/z 468.7(M+H) ⁺ .

tert-Butyl N-[2-(3-formylcyclobutoxy)ethyl]carbamate (Intermediate HP)

Step 1 - 3-(benzyloxymethyl)cyclobutanol

To a solution of 3-(benzyloxymethyl)cyclobutanone (5.00 g, 26.2 mmol, CAS#172324-67-3) in THF (50 mL) at −70° C. with stirring, a solution of lithium; tris-sec-butylboranide (9.99 g, 52.5 mmol) was added dropwise while maintaining the reaction temperature below −65° C. The reaction mixture was allowed to warm to 25° C. for 16 h. Upon completion, the reaction was quenched with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were acidified with 2N aqueous HCl (30 mL) and stirred at 25° C. for 3 h. The organic layers were then washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by column chromatography ( _SiO2 , PE/EA = 10/1) to give the title compound (3.50 g, 69% yield) as a yellow oil.1H ^NMR (400 MHz, _CDCl3 ) δ 7.38 - 7.28 (m, 5H), 4.55 - 4.51 (m, 2H), 4.19 - 4.10 (m, 1H), 3.48 - 3.43 (m, 2H), 2.53 - 2.39 (m, 2H), 2.15 - 2.07 (m, 1H), 1.76 - 1.65 (m, 2H).

Step 2 - 4-Nitrobenzoic acid [3-(benzyloxymethyl)cyclobutyl]

To a solution of 3-(benzyloxymethyl)cyclobutanol (3.50 g, 18.2 mmol) and 4-nitrobenzoic acid (6.08 g, 36.4 mmol, CAS#1044278-58-1) in THF (100 mL) was added _PPh3 (9.55 g, 36.4 mmol). Then, a solution of DEAD (6.34 g, 36.4 mmol) in THF (60 mL) was added dropwise to the above solution at 0 °C. The mixture was degassed and purged with _N2 three times and the mixture was stirred at 25 °C for 16 h. Upon completion, the reaction was quenched with water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the organic liquid was concentrated in reduced pressure. The residue was purified by column chromatography ( _SiO2 , PE/EA = 92/8) to give the title compound (3.00 ^g , 48% yield) as a white solid.1H NMR (400 MHz, _CDCl3 ) δ 8.32 - 8.28 (m, 2H), 8.24 - 8.20 (m, 2H), 7.41 - 7.28 (m, 5H), 5.37 (q, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.55 (d, J = 6.4 Hz, 2H), 2.73 - 2.62 (m, 1H), 2.46 - 2.38 (m, 4H).

Step 3 - 3-(benzyloxymethyl)cyclobutanol

To a solution of 3-(benzyloxymethyl)cyclobutyl 4-nitrobenzoate (3 g, 8.79 mmol) in a mixture of dioxane (30 mL) and H ₂ O (15 mL) was added LiOH.H ₂ O (737 mg, 17.5 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was diluted with H ₂ O (50 mL) and extracted with EA (3×50 mL). The organic layer was washed with brine (2×50 mL). Drying over anhydrous sodium sulfate, filtering and concentrating in vacuum afforded the title compound (1.69 g, 100% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.39 - 7.27 (m, 5H), 4.54 (s, 2H), 4.44 - 4.36 (m, 1H), 3.47 (d, J = 7.2 Hz, 2H), 2.58 - 2.43 (m, 1H), 2.25 - 2.18 (m, 2H), 2.11 - 2.03 (m, 2H).

Step 4 - 2-[3-(benzyloxymethyl)cyclobutoxy]ethyl acetate

To a solution of 3-(benzyloxymethyl)cyclobutanol (1.69 g, 8.79 mmol) in DCM (40 mL) was added diacetoxyrhodium (388 mg, 879 umol) and ethyl 2-diazoacetate (4.01 g, 35.1 mmol, CAS#623-73-4). The mixture was degassed and purged with N ₃ three times, and the mixture was stirred at 25° C. under N ₂ atmosphere for 16 h. Upon completion, the mixture was diluted with H ₂ O (50 mL) and extracted with DCM (3×50 mL). The organic layer was then washed with brine (3×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , PE/EA=100/1 to 10/1) to give the title compound (2.40 g, 98% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.39 - 7.28 (m, 5H), 4.53 (s, 2H), 4.24 (d, J = 3.2 Hz, 2H), 4.17 - 4.14 (m, 1H), 3.97 (s, 2H), 3.46 (d, J = 6.8 Hz, 2H), 2.57 - 2.46 (m, 1H), 2.24 - 2.13 (m, 4H), 1.31 - 1.29 (m, 3H).

Step 5 - 2-[3-(benzyloxymethyl)cyclobutoxy]acetamide

To a solution of ethyl 2-[3-(benzyloxymethyl)cyclobutoxy]acetate (2.40 g, 8.62 mmol) in MeOH (20 mL) was added NH ₃ .H ₂ O (35.6 g, 284 mmol, 28% solution). The mixture was stirred at 70 °C for 16 h. Upon completion, the mixture was concentrated in vacuum, then dissolved in EA (20 mL), diluted with H ₂ O (30 mL) and extracted with EA (3 x 20 mL). The organic layer was then washed with brine (3 x 20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the liquid was concentrated in vacuum to give the title compound (1.60 g, 74% yield) as a brown solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.40 - 7.28 (m, 5H), 6.53 (s, 1H), 5.76 (s, 1H), 4.54 (s, 2H), 4.13 (q, J = 6.4 Hz, 1H), 3.84 (s, 2H), 3.47 (d, J = 6.4 Hz, 2H), 2.60 - 2.48 (m, 1H), 2.18 - 2.11 (m, 4H).

Step 6 - 2-[3-(benzyloxymethyl)cyclobutoxy]ethanamine

To a solution of 2-[3-(benzyloxymethyl)cyclobutoxy]acetamide (1.60 g, 6.42 mmol) in THF (18 mL) was added BH ₃ -Me ₂ S (10 M, 6.42 mL) at 25° C. The mixture was then stirred at 60° C. for 16 h. Upon completion, the mixture was quenched with MeOH (3×10 mL) and refluxed for 20 min (3 times), then concentrated in vacuo to give the title compound (1.50 g, 99% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 236.1 (M+H) ⁺ .

Step 7 - tert-butyl N-[2-[3-(benzyloxymethyl)cyclobutoxy]ethyl]carbamate

To a solution of 2-[3-(benzyloxymethyl)cyclobutoxy]ethanamine (1.50 g, 6.37 mmol) in DCM (20 mL) was added TEA (967 mg, 9.56 mmol) and Boc ₂ O (1.53 g, 7.01 mmol). The mixture was stirred at 25° C. for 16 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE/EA=40/1) to give the title compound (1.00 g, 46% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.38 - 7.25 (m, 5H), 6.76 (t, J = 5.2 Hz, 1H), 4.47 (s, 2H), 4.00 (q, J = 6.8 Hz, 1H), 3.42 (d, J = 6.8 Hz, 2H), 3.23 (t, J = 6.0 Hz, 2H), 3.02 (q, J = 6.0 Hz, 2H), 2.42 - 2.33 (m, 1H), 2.00 - 1.94 (m, 4H), 1.37 (s, 9H).

Step 8 - tert-butyl N-[2-[3-(hydroxymethyl)cyclobutoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[3-(benzyloxymethyl)cyclobutoxy]ethyl]carbamate (430 mg, 1.28 mmol) in MeOH (5 mL) was added Pd/C (400 mg, 1.28 mmol, 10 wt%) and Pd(OH) ₂ (430 mg, 612 umol, 20 wt%) under Ar atmosphere. The mixture was then stirred at 50° C. under H ₂ (50 psi) for 16 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (310 mg, 98% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 4.90 (s, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.64 (d, J = 6.8 Hz, 2H), 3.41 - 3.36 (m, 2H), 3.33 - 3.27 (m, 2H), 2.41 (q, J = 6.8, 13.6 Hz, 1H), 2.12 - 2.09 (m, 2H), 1.79 - 1.54 (m, 2H), 1.45 (s, 9H).

Step 9 - tert-butyl N-[2-(3-formylcyclobutoxy)ethyl]carbamate

To a solution of tert-butyl N-[2-[3-(hydroxymethyl)cyclobutoxy]ethyl]carbamate (310 mg, 1.26 mmol) in DCM (5 mL) was added DMP (803 mg, 1.90 mmol). The mixture was stirred at 25° C. for 2 h. Upon completion, the mixture was quenched with Na ₂ S ₂ O ₃ 5H ₂ O (10 mL), washed with NaHCO ₃ solution (3×20 mL) and extracted with DCM (3×20 mL). The organic layer was washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the liquid was concentrated in vacuo to give the title compound (307 mg, 99% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.72 (d, J = 2.0 Hz, 1H), 6.82 - 6.75 (m, 1H), 4.07 - 3.93 (m, 1H), 3.05 - 3.00 (t, J = 6.0 Hz, 2H), 3.05 - 3.00 (m, 2H), 2.46 - 2.39 (m, 3H), 2.09 - 2.05 (m, 2H), 1.37 (s, 9H).

3-[5-[1-[[3-(2-aminoethoxy)cyclobutyl]methyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HQ)

Step 1 - N-[2-[3-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclobutoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-(3-formylcyclobutoxy)ethyl]carbamate (307 mg, 1.26 mmol, Intermediate HP) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (575 mg, 1.26 mmol, TFA, Intermediate DB) in a mixture of THF (8 mL) and DMF (2 mL) was added TEA (255 mg, 2.52 mmol). The mixture was stirred at −10° C. for 5 min. Afterwards, AcOH (227 mg, 3.79 mmol) was added to the solution and the mixture was then stirred at −10° C. for 25 min. NaBH(OAc) ₃ (534 mg, 2.52 mmol) was then added and the mixture was stirred at −10° C. for 3.5 h. Upon completion, the mixture was quenched with _H2O (3 mL) and then the mixture was concentrated in vacuo. The crude product was purified by reverse phase (0.1% TFA) to give the title compound (187 mg, 27% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.09 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.83 - 6.74 (m, 1H), 5.40 - 5.32 (m, 1H), 3.54 - 3.49 (m, 2H), 3.34 (s, 3H), 3.29 - 3.26 (m, 2H), 3.21 - 3.17 (m, 1H), 3.09 - 3.00 (m, 4H), 2.93 - 2.82 (m, 2H), 2.73 - 2.66 (m, 1H), 2.48 - 2.36 (m, 2H), 2.26 - 2.18 (m, 1H), 2.17 - 2.08 (m, 2H), 2.02 - 1.87 (m, 6H), 1.74 - 1.60 (m, 2H), 1.37 (s, 9H). LC-MS(ESI ⁺ )m/z 570.4(M+H) ⁺ .

Step 2 - 3-[5-[1-[[3-(2-aminoethoxy)cyclobutyl]methyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[3-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclobutoxy]ethyl]carbamate (80.0 mg, 140 umol) in DCM (1 mL) was added TFA (308 mg, 2.70 mmol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (80.0 mg, 97% yield, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 470.1 (M+H) ⁺ .

3-[3-Methyl-4-[methyl(4-piperidylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HR)

Step 1 - tert-Butyl-4-[[methyl-(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]piperidine-1-carboxylate

A mixture of 4-bromo-3-methyl-1H-benzimidazol-2-one (100 mg, 440 umol, synthesized by steps 1-3 of Intermediate H), tert-butyl 4-(methylaminomethyl)piperidine-1-carboxylate (100 mg, 440 umol, CAS# 138022-02-3), Cs ₂ CO ₃ (287 mg, 880 umol), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (38.0 mg, 44.0 umol) and 4A molecular sieves in dioxane (2 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 110 °C under N ₂ atmosphere for 16 h. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 55%-70%, 26 min) to give the title compound (170 mg, 33% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.81 (s, 1H), 6.93 - 6.83 (m, 2H), 6.75 - 6.68 (m, 1H), 3.90 (d, J = 11.2 Hz, 2H), 3.54 (s, 3H), 2.81 (d, J = 6.4 Hz, 2H), 2.63 (d, J = 3.2 Hz, 1H), 2.57 (s, 3H), 1.65 - 1.65 (m, 1H), 1.69 (d, J = 10.4 Hz, 3H), 1.37 (s, 9H), 1.04 - 0.95 (m, 2H). LC-MS(ESI ⁺ )m/z 374.2(M+H) ⁺ .

Step 2 - 4-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-[[methyl-(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]piperidine-1-carboxylate (170 mg, 454 umol) in THF (1 mL) was added t-BuOK (92.0 mg, 817 umol) dropwise at −10° C. After addition, the mixture was stirred at this temperature for 30 minutes, and then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (225 mg, 590 umol, Intermediate G) in THF (1 mL) was added dropwise at −10° C. The resulting mixture was stirred at −10° C. for 12 hours. Upon completion, the mixture was quenched with NH ₄ Cl (2 mL), diluted with H ₂ O (8 mL) and extracted with EA (2×5 mL). The organic layer was then washed with brine (2×3 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound (274 mg, 100% yield) as a red oil. LC-MS (ESI ⁺ ) m/z 606.2 (M+H) ⁺ .

Step 3 - 3-[3-methyl-4-[methyl(4-piperidylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]piperidine-1-carboxylate (270 mg, 446 umol) in TfOH (0.3 mL) was added TFA (3.70 g, 32.4 mmol, 2.4 mL). The mixture was then stirred at 70° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (170 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 386.2 (M+H) ⁺ .

Step 4 - 4-[[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of 3-[3-methyl-4-[methyl(4-piperidylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (170 mg, 441 umol) in DCM (1 mL) was added TEA (134 mg, 1.32 mmol, 185 uL) and tert-butyl tert-butoxycarbonyl carbonate (106 mg, 485 umol, 112 uL). The mixture was stirred at 25° C. for 3 h. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 2/1) to give the title compound (200 mg, 87% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.24 (s, 1H), 7.03 - 6.97 (m, 1H), 6.94 - 6.88 (m, 1H), 6.58 (d, J = 8 Hz, 1H), 5.23 (dd, J = 5.2, 12.4 Hz, 1H), 4.13 (d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 2.97 - 2.71 (m, 6H), 2.66 (s, 3H), 2.27 - 2.19 (m, 1H), 2.05 (s, 1H), 1.75 (d, J = 12 Hz, 2H), 1.46 (s, 9H), 1.30 - 1.24 (m, 2H), 1.17 (s, 2H). LC-MS(ESI ⁺ )m/z 486.0(M+H) ⁺ .

Step 5 - 3-[3-methyl-4-[methyl(4-piperidylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]piperidine-1-carboxylate (90.0 mg, 185 umol) in DCM (0.5 mL) was added TFA (578 mg, 5.06 mmol, 375 uL). The mixture was stirred at 25° C. for 2 hours. Upon completion, the mixture was concentrated in vacuo to give the title compound (71 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 386.3 (M+H) ⁺ .

3-[3-Methyl-4-[methyl-[[1-(4-piperidyl)-4-piperidyl]methyl]amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HS)

Step 1 - 4-[4-[[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]-1-piperidyl]piperidine-1-carboxylate tert-butyl

To a solution of 3-[3-methyl-4-[methyl(4-piperidylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (71 mg, 184 umol, intermediate HR) and tert-butyl 4-oxopiperidine-1-carboxylate (367 mg, 1.84 mmol, CAS#79009-07-3) in THF (3 mL) was added KOAc (362 mg, 3.68 mmol) slowly at 0° C. Then NaBH(OAc) ₃ (390 mg, 1.84 mmol) was added dropwise at 0° C. and the resulting mixture was stirred at 0° C. for 12 hours. Upon completion, the mixture was concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 10 min) to give the title compound (70.0 mg, yield 67%) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.04 (s, 1H), 7.03 - 6.98 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.26 - 5.18 (m, 1H), 4.33 - 4.20 (m, 2H), 3.73 (s, 3H), 3.52 - 3.33 (m, 3H), 3.25 - 3.18 (m, 1H), 3.00 - 2.93 (m, 2H), 2.69 - 2.66 (m, 5H), 2.28 - 2.22 (m, 1H), 2.15 - 2.08 (m, 2H), 2.06 - 1.93 (m, 5H), 1.66 - 1.58 (m, 6H), 1.45 (s, 9H). LC-MS(ESI ⁺ )m/z 569.3(M+H) ⁺ .

Step 2 - 3-[3-methyl-4-[methyl-[[1-(4-piperidyl)-4-piperidyl]methyl]amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[4-[[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]-1-piperidyl]piperidine-1-carboxylate (30.0 mg, 52.8 umol) in DCM (0.5 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (24 mg, 98% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 469.3 (M+H) ⁺ .

tert-Butyl 6-(2-oxoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate HT)

To a solution of tert-butyl 6-(2-hydroxyethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 971 umol, synthesized by steps 1-2 of intermediate FE) in DCM (3 mL) was added DMP (535 mg, 1.26 mmol). The mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (0.1 mL) at 25° C., then diluted with H ₂ O (5 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (248 mg, 99% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.53 - 9.51 (m, 1H), 4.04 - 3.98 (m, 1H), 3.76 (d, J = 18.6 Hz, 4H), 3.30 (s, 2H), 2.43 - 2.34 (m, 2H), 2.00 - 1.91 (m, 2H), 1.33 (s, 9H).

3-[5-[1-[2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HU)

Step 1 - 6-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl

To a solution of tert-butyl 6-(2-oxoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (240 mg, 940 μmol, Intermediate HT), 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (284 mg, 752 μmol, HCl, Intermediate DB) in THF (0.5 mL), DMF (0.5 mL) was added KOAc (923 mg, 9.40 mmol) and NaBH(OAc) ₃ (398 mg, 1.88 mmol). The mixture was stirred at 0° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 9 min) to give the title compound (100 mg, 12% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 583.0 (M+H) ⁺ .

Step 2 - 3-[5-[1-[2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 6-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (80 mg, 137 umol) in DCM (0.4 mL) was added TFA (616 mg, 5.40 mmol). The mixture was stirred at 25° C. for 0.2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (65 mg, 79% yield, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 482.7 (M+H) ⁺ .

1-[4-[4-(2-aminoethyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate HV)

Step 1 - tert-butyl N-[2-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]ethyl]carbamate

A mixture of 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (500 mg, 1.28 mmol, intermediate DS), tert-butyl N-[2-(4-piperidyl)ethyl]carbamate (293 mg, 1.28 mmol, CAS# 165528-81-4), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (165 mg, 192 umol, CAS# 1435347-24-2), and Cs ₂ CO ₃ (837 mg, 2.57 mmol) in dioxane (5 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100° C. under N ₂ atmosphere for 16 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (200 mg, 29% yield) as a slightly yellow solid. LC-MS (ESI ⁺ ) m/z 537.4 (M+H) ⁺ .

Step 2 - 1-[4-[4-(2-aminoethyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]ethyl]carbamate (50 mg, 93.1 umol) in TFA (0.8 mL) and TfOH (0.1 mL). The mixture was stirred at 70° C. for 1 h. Upon completion, the mixture was concentrated in vacuo and DMSO (1 mL) and DIEA were added until pH=8. The mixture was then diluted with water and lyophilized to give the title compound (30 mg, 17% yield) as a slightly yellow solid. LC-MS (ESI ⁺ ) m/z 317.0 (M+H) ⁺ .

Spiro[2.4]heptan-7-amine (Intermediate HW)

Step 1 - Spiro[2.4]heptan-7-ol

To a solution of spiro[2.4]heptan-7-one (4.50 g, 40.8 mmol, CAS#5771-32-4) in EtOH (40 mL) was added NaBH ₄ (3.91 g, 103 mmol) at 0 °C. The reaction was then stirred at 25 °C for 2 h. Upon completion, the reaction was quenched with NH ₄ Cl (10 mL). The mixture was diluted with EA (400 mL), washed with water (200 mL x 3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give the title compound (2.91 g, 63% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 4.28 (d, J = 4.4 Hz, 1H), 3.51 - 3.45 (m, 1H), 1.93 - 1.83 (m, 1H), 1.81 - 1.70 (m, 2H), 1.66 - 1.49 (m, 2H), 1.43 - 1.33 (m, 1H), 0.77 - 0.69 (m, 1H), 0.43 - 0.29 (m, 3H).

Step 2 - 2-spiro[2.4]heptan-7-ylisoindoline-1,3-dione

To a solution of spiro[2.4]heptan-7-ol (2.40 g, 21.4 mmol), isoindoline-1,3-dione (3.78 g, 25.6 mmol, CAS#85-41-6), and PPh ₃ (8.42 g, 32.0 mmol) in THF (60 mL) was added DIAD (6.49 g, 32.0 mmol) at 25 °C under N _2. The reaction was stirred at 60 °C for 16 h. Upon completion, ice water (100 mL) was added to the reaction. The mixture was extracted with EA (200 mL) and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 10/1) to give the title compound (1.7 g, 32% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.83 (s, 4H), 4.32 (t, J = 8.0 Hz, 1H), 2.26 - 2.10 (m, 3H), 2.02 - 1.93 (m, 1H), 1.80 - 1.67 (m, 1H), 1.49 - 1.34 (m, 1H), 0.63 - 0.54 (m, 1H), 0.51 - 0.41 (m, 2H), 0.32 - 0.24 (m, 1H).

Step 3 - Spiro[2.4]heptan-7-amine

To a solution of 2-spiro[2.4]heptan-7-ylisoindoline-1,3-dione (1.4 g, 5.8 mmol) in THF (30 mL) was added NH ₂ NH _{2.H 2} O (1.66 g, 33.1 mmol). The reaction was stirred at 60° C. for 3 h. Upon completion, the reaction was diluted with THF (30 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (550 mg, 85% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 2.84 (t, J = 5.6 Hz, 1H), 2.13 - 2.02 (m, 1H), 1.88 - 1.78 (m, 2H), 1.76 - 1.64 (m, 1H), 1.48 - 1.42 (m, 2H), 1.28 (s, 2H), 0.64 - 0.57 (m, 1H), 0.49 - 0.29 (m, 3H).

4-[(6-chloro-7-oxo-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate HX)

Step 1 - 5-Bromo-2-chloro-N-spiro[2.4]heptan-7-yl-pyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloro-pyrimidine (983 mg, 4.32 mmol, CAS#36082-50-5) and TEA (567 mg, 5.61 mmol) in ACN (15 mL) was added spiro[2.4]heptan-7-amine (480 mg, 4.32 mmol, intermediate HW) at 0° C. The reaction was then stirred at 25° C. for 16 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (50 mL×2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 30/1) to give the title compound (505 mg, 38% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 303.7 (M+H) ⁺ .

Step 2 - N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-spiro[2.4]heptan-7-yl-pyrimidine-2,4-diamine

To a solution of 5-bromo-2-chloro-N-spiro[2.4]heptan-7-yl-pyrimidin-4-amine (450 mg, 1.49 mmol) and 4-benzylsulfanyl-2-methyl-aniline (375 mg, 1.64 mmol, intermediate DE) in IPA (10 mL) was added TFA (3.39 g, 29.7 mmol) under _N2 . The reaction was stirred at 80 °C under _N2 for 16 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (70 mL) and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (400 mg, 54% yield) as a red solid. LC-MS (ESI ⁺ ) m/z 496.9 (M+H) ⁺ .

Step 3 - (E)-3-[2-(4-benzylsulfanyl-2-methyl-anilino)-4-(spiro[2.4]heptan-7-ylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester

To a mixture of N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-spiro[2.4]heptan-7-yl-pyrimidine-2,4-diamine (340 mg, 686 umol), TEA (208 mg, 2.06 mmol) and Pd(PPh ₃ ) ₄ (158 mg, 137 umol) in DMF (3.5 mL) was added methyl prop-2-enoate (0.54 g, 6.27 mmol). The reaction was then stirred at 90 °C under N ₂ for 16 h. Upon completion, the reaction was diluted with water (50 mL) and extracted with EA (70 mL x 2). The organic layer was washed with water (50 mL x 3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (200 mg, 58% yield) as a brown oil: LC-MS (ESI ⁺ ) m/z 501.3 (M+H) ⁺ .

Step 4 - 2-(4-benzylsulfanyl-2-methyl-anilino)-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one

To a solution of methyl (E)-3-[2-(4-benzylsulfanyl-2-methyl-anilino)-4-(spiro[2.4]heptan-7-ylamino)pyrimidin-5-yl]prop-2-enoate (180 mg, 359 umol) in DMF (3 mL) was added t-BuOK (121 mg, 1.08 mmol) at 25° C. and stirred for 0.5 h. The reaction was then stirred at 120° C. for 2 h. Upon completion, the reaction was diluted with EA (40 mL). The organic layer was washed with water (30 mL×3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (80 mg, 47% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 469.6 (M+H) ⁺ .

Step 5 - 4-[(6-chloro-7-oxo-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (80.0 mg, 170 umol) in HOAc (0.1 mL) and ACN (1 mL) was added NCS (91.1 mg, 682 umol) and H ₂ O (30.7 ug, 1.71 umol) in the dark. The reaction was stirred at 25° C. in the dark for 0.5 h. Upon completion, the reaction was diluted with EA (50 mL). The organic layer was washed with water (50 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 2/1) to give the title compound (60 mg, 73% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 479.0 (M+H) ⁺ .

tert-Butyl 4-(4-piperidyloxymethyl)piperidine-1-carboxylate (Intermediate HY)

Step 1 - 4-(4-pyridyloxymethyl)piperidine-1-carboxylate tert-butyl

_A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol, CAS#123855-51-6), pyridin-4-ol (4.42 g, 46.5 mmol, CAS#626-64-2), PPh3 (25.0 g, 93.0 mmol), DIAD (19.0 g, 93.0 mmol, 18.0 mL) in THF (50 mL) was degassed and purged with _N2 three times, then the mixture was stirred at 25 °C under _N2 atmosphere for 16 h. Upon completion, the mixture was diluted with _H2O (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA) to give the title compound (4.9 g, 37% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.44 (d, J = 6.0 Hz, 2H), 6.82 (d, J = 6.0 Hz, 2H), 4.18 (d, J = 4.0 Hz, 2H), 3.87 (d, J = 6.4 Hz, 2H), 2.76 (t, J = 12.4 Hz, 2H), 2.09 - 1.90 (m, 1H), 1.82 (d, J = 12.8 Hz, 2H), 1.48 (s, 9H), 1.35 - 1.23 (m, 2H). LC-MS(ESI ⁺ )m/z 293.3(M+H) ⁺ .

Step 2 - 4-(4-piperidyloxymethyl)piperidine-1-carboxylate tert-butyl

A mixture of tert-butyl 4-(4-pyridyloxymethyl)piperidine-1-carboxylate (2 g, 6.84 mmol), _PtO2 (1.55 g, 6.84 mmol), HOAc (8.40 g, 140 mmol, 8.00 mL) in EtOH (20 mL) was degassed and purged with _H2 three times. This mixture was then stirred at 40 °C under an atmosphere of _H2 for 16 h. Upon completion, the mixture was filtered and concentrated in vacuo to provide the title compound (2.00 g, 82% yield, HOAc salt) as a white oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 5.35 - 4.85 (m, 1H), 3.92 (d, J = 12.0 Hz, 2H), 3.41 - 3.32 (m, 1H), 3.27 - 3.20 (m, 2H), 3.00 - 2.87 (m, 2H), 2.66 (t, J = 9.2 Hz, 3H), 2.34 - 2.19 (m, 1H), 1.88 - 1.76 (m, 1H), 1.63 (d, J = 12.0 Hz, 3H), 1.49 - 1.41 (m, 2H), 1.38 (s, 9H), 1.09 - 0.93 (m, 3H). LC-MS(ESI ⁺ )m/z 299.1(M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[4-(4-piperidylmethoxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate HZ)

Step 1 - 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]oxymethyl]piperidine-1-carboxylate tert-butyl

A mixture of tert-butyl 4-(4-piperidyloxymethyl)piperidine-1-carboxylate (50 mg, 168 umol, Intermediate HY), 4-bromo-3-methyl-1H-benzimidazol-2-one (150 mg, 661 umol, synthesized by steps 1-3 of Intermediate H), Cs ₂ CO ₃ (1.35 g, 4.13 mmol), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (71.0 mg, 83.0 umol) and 4A molecular sieves in dioxane (1 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 12 h. Upon completion, the mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 10 min) to give the title compound (70 mg, 9% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 445.3 (M+H) ⁺ .

Step 2 - 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]oxymethyl]piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]oxymethyl]piperidine-1-carboxylate (100 mg, 225 umol) in THF (1 mL) was added t-BuOK (46 mg, 405 umol) and [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (112 mg, 293 umol, intermediate CY). The mixture was stirred at −10° C. for 6 h. Upon completion, the mixture was quenched with NH ₄ Cl (1 mL), diluted with H ₂ O (8 mL) and extracted with EA (2×5 mL). The organic layer was then washed with brine (2×3 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate=0:1) to afford the title compound (130 mg, 77% yield) as a red oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.21 (d, J = 8.8 Hz, 2H), 6.95 - 6.88 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 5.6 Hz, 1H), 5.53 - 5.46 (m, 1H), 4.86 - 4.70 (m, 2H), 3.98 - 3.89 (m, 2H), 3.72 (s, 3H), 3.71 (d, J = 1.6 Hz, 1H), 3.62 (s, 3H), 3.12 - 3.00 (m, 2H), 2.84 - 2.69 (m, 5H), 2.06 - 1.98 (m, 3H), 1.88 - 1.81 (m, 1H), 1.74 - 1.60 (m, 4H), 1.59-1.51 (m, 1H), 1.39 (s, 9H), 1.24 (s, 3H), 1.09 - 0.99 (m, 2H). LC-MS(ESI ⁺ )m/z 676.4(M+H) ⁺ .

Step 3 - 3-[3-methyl-2-oxo-4-[4-(4-piperidylmethoxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]oxymethyl]piperidine-1-carboxylate (30 mg, 44.4 umol) in TFA (0.8 mL) was added TfOH (170 mg, 1.13 mmol, 100 uL). The mixture was stirred at 70° C. for 2 h. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA=0:1) to give the title compound (20 mg, 97% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 456.1 (M+H) ⁺ .

tert-Butyl N-[2-(4-formylcyclohexoxy)ethyl]-N-methyl-carbamate (Intermediate IA)

Step 1 - N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]-N-methyl-tert-butyl carbamate

To a solution of tert-butyl N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]carbamate (400 mg, 781 umol, synthesized by steps 1-6 of intermediate DP) in THF (4 mL) was added NaH (93.8 mg, 2.34 mmol, 60% dispersion in mineral oil) and MeI (389 uL, 6.25 mmol) at 0° C., then the mixture was stirred at 25° C. for 10 h. Upon completion, the mixture was quenched with sat. NH ₄ Cl (3 mL), then washed with water (50 mL) and extracted with EA (50 mL×3). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=100:3 to 20:1) to give the title compound (300 mg, yield 73%) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.67 - 7.65 (m, 4H), 7.47 - 7.33 (m, 6H), 3.57 - 3.56 (m, 2H), 3.47 - 3.45 (m, 2H), 3.37 (s, 2H), 3.19 - 3.14 (m, 1H), 2.93 (s, 3H), 2.09 - 2.00 (m, 2H), 1.85 - 1.82 (m, 2H), 1.58 - 1.51 (m, 1H), 1.47 (s, 9H), 1.24 - 1.16 (m, 2H), 1.06 (s, 9H), 1.03 - 0.94 (m, 2H).

Step 2 - N-[2-[4-(hydroxymethyl)cyclohexoxy]ethyl]-N-methyl-carbamic acid tert-butyl

To a solution of tert-butyl N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexoxy]ethyl]-N-methyl-carbamate (300 mg, 570 umol) in THF (3 mL) was added TBAF (1 M, 855 uL) and the mixture was then stirred at 25° C. for 2 h. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=20:1-2:1) to give the title compound (150 mg, 91% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 3.58 (s, 2H), 3.46 - 3.45 (m, 2H), 3.36 - 3.35 (m, 2H), 3.25 - 3.15 (m, 1H), 2.92 (s, 3H), 2.07 - 2.04 (m, 2H), 1.85 - 1.82 (m, 2H), 1.64 - 1.53 (m, 1H), 1.46 (s, 9H), 1.27 - 1.17 (m, 2H), 1.05 - 0.91 (m, 2H).

Step 3 - N-[2-(4-formylcyclohexoxy)ethyl]-N-methyl-carbamic acid tert-butyl

To a solution of tert-butyl N-[2-[4-(hydroxymethyl)cyclohexoxy]ethyl]-N-methyl-carbamate (50.0 mg, 174 umol) in DCM (1 mL) was added DMP (110 mg, 261 umol) at 0° C., then the mixture was stirred at 25° C. for 2 h. Upon completion, the mixture was quenched with sodium thiosulfate pentahydrate (5 mL) and NaHCO ₃ (5 mL), then extracted with DCM (10 mL×3). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated in vacuum to give the title compound (30.0 mg, 60% yield) as a yellow oil.

3-[3-Methyl-5-[1-[[4-[2-(methylamino)ethoxy]cyclohexyl]methyl]-4-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate IB)

Step 1 - N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclohexoxy]ethyl]-N-methyl-carbamic acid tert-butyl

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (38.4 mg, 84.1 umol, TFA, Intermediate DB) in THF (1 mL) was added TEA (14.6 uL, 105 umol). Then N-[2-(4-formylcyclohexoxy)ethyl]-N-methyl-tert-butylcarbamate (30.0 mg, 105 umol, Intermediate IA) and HOAc (6.01 uL, 105 umol) were added and the mixture was stirred at −10° C. for 0.5 h. Then NaBH(OAc) ₃ (33.4 mg, 158 umol) was added and the mixture was stirred at −10° C. for 1.5 h. Upon completion, the mixture was concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 8 min) to give the title compound (10.0 mg, 16% yield) as a colorless gum. LC-MS (ESI ⁺ ) m/z 612.4 (M+H) ⁺ .

Step 2 - 3-[3-methyl-5-[1-[[4-[2-(methylamino)ethoxy]cyclohexyl]methyl]-4-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclohexoxy]ethyl]-N-methyl-carbamate (10.0 mg, 16.3 umol) in DCM (0.5 mL) was added TFA (0.2 mL, 2.70 mmol) and the mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (10.0 mg, 97% yield, TFA) as a colorless oil. LC-MS (ESI ⁺ ) m/z 512.2 (M+H) ⁺ .

tert-Butyl N-[5-[(2-chloroacetyl)amino]pentyl]carbamate (Intermediate IC)

To a solution of tert-butyl N-(5-aminopentyl)carbamate (500 mg, 2.47 mmol, 514 ul, CAS#51644-96-3) in THF (5 mL) was added 2-chloroacetyl chloride (418 mg, 3.71 mmol, 29.0 uL, CAS#79-04-9) and the mixture was stirred at 25° C. for 1 hour. Upon completion, the mixture was concentrated in vacuo to give the title compound (500 mg, 72% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 178.9 (M+H) ⁺ .

N-(5-aminopentyl)-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide (Intermediate ID)

Step 1 - tert-butyl N-[5-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]pentyl]carbamate

To a solution of tert-butyl N-[5-[(2-chloroacetyl)amino]pentyl]carbamate (500 mg, 1.79 mmol, Intermediate IC) and 4-(2,6-dibenzyloxy-3-pyridyl)phenol (206 mg, 538 umol, Intermediate IE) in THF (5 mL) was added NaOH (322 mg, 8.07 mmol). The mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was diluted with H ₂ O (0.5 mL) and then concentrated in vacuo to afford the title compound (183 mg, 16% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.05 (t, J = 5.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.50 - 7.29 (m, 12H), 6.97 (d, J = 8.4 Hz, 2H), 6.79 - 6.71 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 5.38 (d, J = 12.8 Hz, 4H), 4.47 (s, 2H), 3.13 - 3.08 (m, 2H), 2.93 - 2.83 (m, 4H), 2.07 (s, 2H), 1.36 (s, 9H), 1.25 - 1.19 (m, 2H). LC-MS(ESI ⁺ )m/z 626.3(M+H) ⁺ .

Step 2 - tert-butyl N-[5-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]pentyl]carbamate

To a solution of tert-butyl N-[5-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]pentyl]carbamate (173 mg, 276 umol) in THF (2.00 mL) was added Pd/C (2.00 mg, 2.76 umol, 10 wt%). The mixture was then stirred at 25° C. under H ₂ for 1 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (48.0 mg, 38% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 347.9 (M-100) ⁺ .

Step 3 - N-(5-aminopentyl)-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide

To a solution of tert-butyl N-[5-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]pentyl]carbamate (48.0 mg, 107 umol) in TFA (1 mL) and DCM (2 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (37.0 mg, 74% yield, TFA) as a colorless oily liquid. LC-MS (ESI ⁺ ) m/z 347.9 (M+H) ⁺ .

4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (Intermediate IE)

_A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.50 g, 22.8 mmol, _CAS #2152673-80-6), 4-bromophenol (3.94 g, 22.8 mmol, CAS#106-41-2), _K2CO3 (9.44 g, 68.3 mmol), and Pd(dppf) _Cl2.CH2Cl2 (1.86 g, 2.28 mmol) in _dioxane (150 mL) and _H2O (30 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 80 °C under _N2 atmosphere for 12 h. Upon completion, the reaction mixture was diluted with _H2O (200 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with aqueous NaCl (200 mL x 2), dried over _Na2SO4 , filtered and concentrated in vacuo to give a residue which was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 10/1 _to 5/1) to give the title compound (7 g, yield 79%) as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.45 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49 - 7.24 (m, 12H), 6.78 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 8.0 Hz, 1H), 5.38 (d, J = 13.2 Hz, 4H); LC-MS(ESI ⁺ ) m/z 384.2(M+H) ⁺ .

tert-Butyl N-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethyl]carbamate (Intermediate IF)

To a solution of tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (500 mg, 2.45 mmol, CAS#127828-22-2) in DCM (5 mL) was added TEA (743 mg, 7.34 mmol). Then 2-chloroacetyl chloride (331.75 mg, 2.94 mmol, CAS#79-04-9) in DCM (3 mL) was added to the mixture at 0 °C. The reaction was stirred at 25 °C for 1 h. Upon completion, the mixture was diluted with DCM (60 mL) and washed with water (50 mL x 3). The organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo to give the title compound (610 mg, 88% yield) as a yellow oil.

N-[2-(2-aminoethoxy)ethyl]-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide (Intermediate IG)

Step 1 - tert-butyl N-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethyl]carbamate (246 mg, 876 umol, intermediate IF) and 4-(2,6-dibenzyloxy-3-pyridyl)phenol (120 mg, 312 umol, intermediate IE) in DMF (4 mL) was added Cs ₂ CO ₃ (305 mg, 938 umol). The reaction was then stirred at 50° C. for 4 h. Upon completion, the mixture was diluted with EA (50 mL) and washed with water (30 mL×3). The organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1). The crude product was then further purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 66%-96%, 10 min) to give the title compound (196 mg, 99% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.08 (m, J = 5.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.45 - 7.41 (m, 2H), 7.40 - 7.23 (m, 8H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 - 6.69 (m, 1H), 6.52 (d, J = 8.0 Hz, 1H), 5.39 (s, 2H), 5.36 (s, 2H), 4.49 (s, 2H), 3.45 - 3.39 (m, 2H), 3.36 (t, J = 6.0 Hz, 2H), 3.27 (s, 1H), 3.05 (m, J = 5.6 Hz, 2H), 1.42 - 1.42 (m, 1H), 1.35 (s, 9H).

Step 2 - tert-butyl N-[2-[2-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy]ethyl]carbamate (100 mg, 159 umol) in MeOH (4 mL) was added Pd/C (50 mg, 159 umol, 10 wt%) under _N2 atmosphere. The suspension was degassed and purged with _H2 three times. The mixture was then stirred at 25°C under _H2 (15 Psi) atmosphere for 2 h. Upon completion, the mixture was diluted with MeOH (10 mL), filtered, and the filtrate was concentrated in vacuo to give the title compound (59 mg, 82% yield) as a colorless solid. LC-MS (ESI ⁺ ) m/z 350.0 (M+H) ⁺ .

Step 3 - N-[2-(2-aminoethoxy)ethyl]-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide

A mixture of tert-butyl N-[2-[2-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]ethoxy]ethyl]carbamate (59 mg, 131 umol) in HCl/EtOAc (4 M, 4 mL) was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (45 mg, 98% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 350.0 (M+H) ⁺ .

tert-Butyl N-[2-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethoxy]ethyl]carbamate (Intermediate IH)

To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (500 mg, 2.01 mmol, CAS#153086-78-3) in DCM (3 mL) was added TEA (840 uL, 6.04 mmol). Then, a solution of 2-chloroacetyl chloride (192 uL, 2.42 mmol, CAS#79-04-9) in DCM (2 mL) was added dropwise at 0° C. and the mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was diluted with DCM (50 mL) and washed with water (40 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and then concentrated in vacuum to give the title compound (550 mg, 84% yield) as a yellow oil.

N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide (Intermediate II)

Step 1 - N-[2-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethoxy]ethyl]carbamate (474 mg, 1.46 mmol, Intermediate IH) and 4-(2,6-dibenzyloxy-3-pyridyl)phenol (280 mg, 730 umol, Intermediate IE) in DMF (5 mL) was added Cs ₂ CO ₃ (713 mg, 2.19 mmol), then the mixture was stirred at 50° C. for 2 h. Upon completion, the mixture was filtered and the filtrate was diluted with EA (40 mL) and washed with water (30 mL×3). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=20:1-1:2) to give the title compound (480 mg, 97% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.24 (s, 1H), 8.07 (t, J = 5.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.46 - 7.41 (m, 2H), 7.40 - 7.32 (m, 7H), 6.97 (d, J = 8.8 Hz, 2H), 6.74 (s, 1H), 6.53 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 5.38 (d, J = 13.6 Hz, 4H), 4.49 (s, 2H), 4.06 (s, 1H), 3.49 - 3.47 (m, 4H), 3.44 - 3.43 (m, 2H), 3.37 - 3.36 (m, 2H), 3.06 - 3.04 (m, 2H), 1.36 (s, 9H). LC-MS(ESI ⁺ )m/z 672.5(M+H) ⁺ .

Step 2 - N-[2-[2-[2-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate (150 mg, 223 umol) in MeOH (1 mL) was added Pd/C (50.0 mg, 10 wt%) under _N2 atmosphere. The mixture was then degassed and charged with _H2 three times and then stirred at 25°C under _H2 (15 psi) for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 90% yield) as a white gum. LC-MS (ESI ⁺ ) m/z 494.0 (M+H) ⁺ .

Step 3 - N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide

A solution of tert-butyl N-[2-[2-[2-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate (50.0 mg, 101 umol) in HCl/dioxane (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (40.0 mg, 91% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 394.0 (M+H) ⁺ .

3-[3-Methyl-2-oxo-5-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate IJ)

Step 1 - 4-[[1-[3-(methylamino)-4-nitro-phenyl]-4-piperidyl]oxy]piperidine-1-carboxylate tert-butyl

A mixture of 5-fluoro-N-methyl-2-nitro-aniline (498 mg, 2.93 mmol, CAS#120381-42-2), TEA (889 mg, 8.79 mmol, 1.22 mL) and tert-butyl 4-(4-piperidyloxy)piperidine-1-carboxylate (1.00 g, 3.52 mmol, CAS#845305-83-1) in DMSO (12 mL) was stirred at 50° C. for 2 h. Upon completion, the reaction mixture was diluted with EA (90 mL) and washed with water (30 mL×3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , PE:EA=3:1 to 1:1) to give the title compound (1.05 g, 82% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.35 (d, J = 4.8 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 6.47 - 6.36 (m, 1H), 5.92 (d, J = 2.4 Hz, 1H), 3.82 - 3.69 (m, 3H), 3.68 - 3.59 (m, 3H), 3.27 - 3.15 (m, 2H), 3.09 - 2.96 (m, 2H), 2.93 (d, J = 4.8 Hz, 3H), 1.92 - 1.82 (m, 2H), 1.79 - 1.69 (m, 2H), 1.51 - 1.42 (m, 2H), 1.39 (s, 9H), 1.36 - 1.27 (m, 2H).

Step 2 - 4-[[1-[4-amino-3-(methylamino)phenyl]-4-piperidyl]oxy]piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-[[1-[3-(methylamino)-4-nitro-phenyl]-4-piperidyl]oxy]piperidine-1-carboxylate (1 g, 2.30 mmol) in THF (20 mL) was added Pd/C (500 mg, 2.30 mmol, 10 wt%) under Ar. The suspension was degassed under reduced pressure and purged with _H2 several times. The mixture was then stirred under _H2 (15 psi) at 25 °C for 5 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the title compound (853 mg, 91% yield) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 6.40 (d, J = 8.0 Hz, 1H), 6.08 - 5.97 (m, 2H), 4.55 - 4.47 (m, 1H), 3.98 (s, 2H), 3.68 - 3.58 (m, 3H), 3.54 - 3.46 (m, 1H), 3.28 - 3.20 (m, 2H), 3.00 (s, 2H), 2.68 (d, J = 5.2 Hz, 3H), 2.67 - 2.60 (m, 2H), 1.92 - 1.82 (m, 2H), 1.81 - 1.71 (m, 2H), 1.57 - 1.47 (m, 2H), 1.39 (s, 9H), 1.35 - 1.25 (m, 2H).

Step 3 - 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-5-yl)-4-piperidyl]oxy]piperidine-1-carboxylate tert-butyl

A mixture of tert-butyl 4-[[1-[4-amino-3-(methylamino)phenyl]-4-piperidyl]oxy]piperidine-1-carboxylate (800 mg, 1.98 mmol) and CDI (480 mg, 2.97 mmol) in ACN (10 mL) was stirred at 80° C. for 4 h. Upon completion, the reaction mixture was concentrated in vacuo to remove ACN (5 mL). The mixture was then added dropwise to water (80 mL) and filtered. The filtered cake was dried in vacuo to afford the title compound (680 mg, 79% yield) as a purple solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.48 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.59 - 6.55 (m, 1H), 3.68 - 3.53 (m, 4H), 3.42 - 3.35 (m, 2H), 3.23 (s, 3H), 3.01 (t, J = 9.6 Hz, 2H), 2.86 - 2.73 (m, 2H), 1.94 - 1.86 (m, 2H), 1.80 - 1.72 (m, 2H), 1.60 - 1.49 (m, 2H), 1.39 (s, 9H), 1.35 - 1.26 (m, 2H).

Step 4 - 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carboxylate tert-butyl

A mixture of tert-butyl 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-5-yl)-4-piperidyl]oxy]piperidine-1-carboxylate (600 mg, 1.39 mmol) and tBuOK (234 mg, 2.09 mmol) in THF (7 mL) was stirred at 0° C. for 0.5 h. Then a mixture of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (797 mg, 2.09 mmol, intermediate G) in THF (5 mL) was added dropwise to the above mixture and the mixture was stirred at 0° C. for 0.5 h. Upon completion, the reaction mixture was diluted with EA (80 mL) and the organic layer was washed with water (50 mL×3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , PE:EA=1:1 to 1:3 to 0:1) to give the title compound (900 mg, yield 97%) as a green semi-solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.20 (d, J = 8.8 Hz, 2H), 6.88 - 6.82 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 6.59 - 6.53 (m, 1H), 5.47 - 5.38 (m, 1H), 4.85 - 4.73 (m, 2H), 3.74 - 3.71 (m, 3H), 3.68 - 3.56 (m, 4H), 3.46 - 3.38 (m, 2H), 3.30 (s, 3H), 3.09 - 2.97 (m, 3H), 2.86 - 2.77 (m, 3H), 2.73 - 2.63 (m, 1H), 2.06 - 2.00 (m, 1H), 1.95 - 1.87 (m, 2H), 1.80 - 1.71 (m, 2H), 1.62 - 1.51 (m, 2H), 1.39 (s, 9H), 1.35 - 1.27 (m, 2H).

Step 5 - 3-[3-methyl-2-oxo-5-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carboxylate (300 mg, 453 umol) and TfOH (1.02 g, 6.80 mmol, 0.6 mL) in TFA (3 mL) was stirred at 70° C. for 2.5 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (251 mg, 99% yield, TFA) as a red oil. LC-MS (ESI ⁺ ) m/z 441.9 (M+H) ⁺ .

3-[5-[4-[[1-(3-aminopropyl)-4-piperidyl]oxy]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate IK)

Step 1 - tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]-1-piperidyl]propyl]carbamate

To a solution of 3-[3-methyl-2-oxo-5-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (250 mg, 450 umol, TFA, Intermediate IJ), TEA (136 mg, 1.35 mmol) and HOAc (108 mg, 1.80 mmol) in DMF (2 mL) and THF (2 mL) was added tert-butyl N-(3-oxopropyl)carbamate (169 mg, 975 umol, Intermediate GM). The mixture was stirred at 25° C. for 0.5 h. NaBH(OAc) ₃ (143 mg, 675 umol) was then added and the mixture was stirred at 25° C. for 1.5 h. Upon completion, the reaction mixture was quenched with water (0.2 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C18 250×50 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 8 min) to give the title compound (140 mg, 51% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.05 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.65 - 6.60 (m, 1H), 5.39 - 5.16 (m, 1H), 3.58 - 3.51 (m, 1H), 3.44 - 3.39 (m, 3H), 3.30 (s, 3H), 2.94 - 2.88 (m, 3H), 2.86 - 2.77 (m, 3H), 2.64 - 2.60 (m, 1H), 2.24 (t, J = 7.2 Hz, 3H), 2.06 - 1.94 (m, 4H), 1.94 - 1.85 (m, 3H), 1.83 - 1.73 (m, 3H), 1.54 - 1.47 (m, 4H), 1.37 (s, 9H).

Step 2 - 3-[5-[4-[[1-(3-aminopropyl)-4-piperidyl]oxy]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]-1-piperidyl]propyl]carbamate (35.0 mg, 58.4 umol) and TFA (359 mg, 3.15 mmol) in DCM (1 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (35.8 mg, 99% yield, TFA) as a colorless oil. LC-MS (ESI ⁺ ) m/z 498.9 (M+H) ⁺ .

tert-Butyl N-[2-[2-[2-(4-piperidylmethoxy)ethoxy]ethoxy]ethyl]carbamate (Intermediate IL)

Step 1 - tert-butyl N-[2-[2-[2-(4-pyridylmethoxy)ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (500 mg, 2.01 mmol, CAS# 139115-92-7) in THF (5 mL) was degassed and purged with N ₃ times. NaH (160 mg, 4.01 mmol, 60% dispersion in mineral oil) was then added to the mixture at 0 °C and the mixture was stirred for 1 h. 4-(Bromomethyl)pyridine (345 mg, 2.01 mmol, CAS# 54751-01-8) was then added and the mixture was stirred at 25 °C under N ₂ atmosphere for 2 h. Upon completion, the reaction mixture was extracted with H ₂ O (10 mL) at 25 °C followed by EA (3 x 10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. This residue was then purified by prep-HPLC (column: Phenomenex C18 250×50 mm×10 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 18%-48%, 8 min) to give the title compound (200 mg, 28% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 341.2 (M+1) ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.58 (d, J = 6.0 Hz, 2H), 7.29 (d, J = 6.0 Hz, 2H), 5.01 (s, 1H), 4.60 (s, 2H), 3.73 - 3.68 (m, 4H), 3.68 - 3.63 (m, 4H), 3.55 (t, J = 4.8 Hz, 2H), 3.32 - 3.31 (m, 2H), 1.44 (s, 9H).

Step 2 - tert-butyl N-[2-[2-[2-(4-piperidylmethoxy)ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[2-(4-pyridylmethoxy)ethoxy]ethoxy]ethyl]carbamate (170 mg, 499 umol) in EtOH (5 mL) and AcOH (525 mg, 8.74 mmol) was added PtO ₂ (113 mg, 499 umol) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ three times. The mixture was stirred under H ₂ (15 Psi) at 40 °C for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (150 mg, 86% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 5.33 - 4.94 (m, 1H), 3.65 - 3.58 (m, 8H), 3.56 - 3.52 (m, 2H), 3.44 - 3.29 (m, 6H), 2.86 - 2.80 (m, 2H), 1.95 - 1.76 (m, 4H), 1.44 (s, 9H), 1.33 - 1.23 (m, 1H).

1-[4-[4-[2-[2-(2-aminoethoxy)ethoxy]ethoxymethyl]-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate IM)

Step 1 - N-[2-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethoxy]ethyl]carbamate tert-butyl

A mixture of tert-butyl N-[2-[2-[2-(4-piperidylmethoxy)ethoxy]ethoxy]ethyl]carbamate (150 mg, 432 umol, Intermediate IL), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (134 mg, 346 umol, Intermediate DS), _Cs2CO3 ( ₅₆₄ mg, 1.73 mmol) and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (37.2 mg, 43.2 umol) in dioxane (2 mL) was degassed and purged with _N2 three times. This mixture was then stirred at 100 °C under _N2 atmosphere for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 29%-59%, 15 min) to give the title compound (70.0 mg, 24% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 655.2 (M+1) ⁺ .

Step 2 - 1-[4-[4-[2-[2-(2-aminoethoxy)ethoxy]ethoxymethyl]-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethoxy]ethyl]carbamate (70.0 mg, 106 umol) in TFA (1.2 mL) was added TfOH (0.396 mg, 2.64 umol). The mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (45.0 mg, 96% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 435.1 (M+1) ⁺ .

tert-Butyl N-[3-[(2-chloroacetyl)amino]propyl]carbamate (Intermediate IN)

To a solution of tert-butyl N-(3-aminopropyl)carbamate (1.00 g, 5.74 mmol, CAS#75178-96-0) in THF (10 mL) was added 2-chloroacetyl chloride (1.30 g, 11.4 mmol). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1.00 g, 70% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.43 - 7.29 (m, 1H) 4.16 - 4.08 (m, 6H) 3.38 (d, J = 6.4 Hz, 2H) 3.19 (s, 2H) 1.80 - 1.63 (m, 2H) 1.45 (s, 9H).

N-(3-aminopropyl)-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide (Intermediate IO)

Step 1 - tert-butyl N-[3-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]propyl]carbamate

To a solution of tert-butyl N-[3-[(2-chloroacetyl)amino]propyl]carbamate (5×100 mg, 5×398 umol, Intermediate IN) in DMF (5×2 mL) was added NaOH (5×63.8 mg, 5×1.60 mmol) and 4-(2,6-dibenzyloxy-3-pyridyl)phenol (5×45.8 mg, 5×119 umol, Intermediate IE). The mixture was stirred at 25° C. for 16 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with EA (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (170 mg, 14% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.58 (d, J = 8.4 Hz, 1H) 7.52 (d, J = 8.8 Hz, 2H) 7.46 - 7.42 (m, 2H) 7.41 - 7.28 (m, 10H) 6.97 (d, J = 8.8 Hz, 2H) 6.48 (d, J = 8 Hz, 1H) 5.44 - 5.36 (m, 4H) 4.54 (s, 2H) 3.42 (d, J = 6.4 Hz, 2H) 3.16 (d, J = 6.4 Hz, 2H) 1.69 - 1.66 (m, 2H) 1.46 - 1.43 (m, 9H). LC-MS(ESI ⁺ )m/z 598.1(M+H) ⁺ .

Step 2 - tert-butyl N-[3-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]propyl]carbamate

To a solution of tert-butyl N-[3-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]propyl]carbamate (115 mg, 192 umol) in THF (2 mL) was added Pd/C (227 mg, 193 umol) under _N2 atmosphere. The suspension was degassed and purged with _H2 three times. The mixture was stirred under _H2 at 25 °C for 2 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (80.0 mg, 99% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 319.9 (M+H) ⁺ .

Step 3 - N-(3-aminopropyl)-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide

To a solution of tert-butyl N-[3-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]propyl]carbamate (80.0 mg, 190 umol) in DCM (1 mL) was added TFA (1.31 g, 11.4 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the title compound (60.0 mg, 99% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 319.9 (M+H) ⁺ .

tert-Butyl N-[7-[(2-chloroacetyl)amino]heptyl]carbamate (Intermediate IP)

To a solution of tert-butyl N-(7-aminoheptyl)carbamate (600 mg, 2.60 mmol, CAS# 99733-18-3) in THF (1 mL) was added TEA (264 mg, 2.60 mmol, 363 uL) and 2-chloroacetyl chloride (353 mg, 3.13 mmol, 249 uL, CAS# 79-04-9). The mixture was stirred at 25° C. for 12 hours. Upon completion, the mixture was concentrated in vacuo to give the title compound (799 mg, 100% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 329.1 (M+H) ⁺ .

N-(7-aminoheptyl)-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide (Intermediate IQ)

Step 1 - tert-butyl N-[7-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]heptyl]carbamate

To a solution of tert-butyl N-[7-[(2-chloroacetyl)amino]heptyl]carbamate (799 mg, 2.60 mmol, intermediate IP) in THF (1 mL) was added NaOH (469 mg, 11.7 mmol) and 4-(2,6-dibenzyloxy-3-pyridyl)phenol (200 mg, intermediate IE). The mixture was stirred at 25 °C for 12 h. Upon completion, the mixture was diluted with H ₂ O (15 mL) and extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 56%-86%, 20 min) to give the title compound (360 mg, 21% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.58 (d, J = 8.0 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.46 - 7.41 (m, 2H), 7.40 - 7.29 (m, 7H), 6.97 - 6.93 (m, 2H), 6.61 (t, J = 5.6 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 5.47 - 5.35 (m, 4H), 4.53 (s, 2H), 3.40 - 3.32 (m, 2H), 3.10 (d, J = 6.0 Hz, 2H), 1.61 - 1.47 (m, 4H), 1.45 (s, 10H), 1.33 (s, 7H). LC-MS(ESI ⁺ )m/z 654.2(M+H) ⁺ .

Step 2 - tert-butyl N-[7-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]heptyl]carbamate

To a solution of tert-butyl N-[7-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]heptyl]carbamate (257 mg, 393 umol) in THF (2 mL) was added Pd/C (47 mg, 39.2 umol, 10 wt%) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 several times. The mixture was then stirred under _H2 (15 psi) at 25 °C for 12 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (150 mg, 81% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.02 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.97 - 6.91 (m, 2H), 6.52 (s, 1H), 4.50 (s, 2H), 3.75 (dd, J = 5.2, 10.0 Hz, 1H), 3.39 - 3.30 (m, 2H), 3.10 (d, J = 6.0 Hz, 2H), 2.80 - 2.62 (m, 2H), 2.39 - 2.12 (m, 3H), 1.45 (s, 9H), 1.44 (s, 3H), 1.31 (s, 6H). LC-MS(ESI ⁺ )m/z 476.0(M+H) ⁺ .

Step 3 - N-(7-aminoheptyl)-2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetamide

To a solution of tert-butyl N-[7-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]heptyl]carbamate (90 mg, 189 umol) in DCM (0.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (70 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 375.7 (M+H) ⁺ .

4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(2-piperazin-1-ylethyl)benzenesulfonamide (Intermediate IR)

Step 1 - 4-[2-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate tert-butyl

To a solution of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (100 mg, 234 umol, intermediate DG) in ACN (1.00 mL) and DMF (1 mL) was added DIEA (30.2 mg, 234 umol, 40.7 uL), 4A molecular sieves (5.00 mg, 234 umol) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (53.0 mg, 234 umol, CAS# 192130-34-0). The mixture was then stirred at 25° C. for 10 minutes. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by pre-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 19%-49%, 9 min) to give the title compound (130 mg, 89% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 620.3 (M+H) ⁺ .

Step 2 - 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(2-piperazin-1-ylethyl)benzenesulfonamide

To a solution of tert-butyl 4-[2-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (89.0 mg, 143 umol) in DCM (1.00 mL), TFA (1.00 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (80.0 mg, 87% yield, TFA) as a brown oily liquid. LC-MS (ESI ⁺ ) m/z 520.1 (M+H) ⁺ .

Benzyl 4-(4-piperidylmethoxy)piperidine-1-carboxylate (Intermediate IS)

Step 1 - 4-(4-pyridyloxymethyl)piperidine-1-carboxylate tert-butyl

A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol, CAS#123855-51-6), pyridin-4-ol (4.42 g, 46.5 mmol, CAS#626-64-2), _PPh3 (25.0 g, 93.0 mmol), and DIAD (19.0 g, 93.0 mmol, 18.0 mL) in THF (50 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 25 °C under _N2 atmosphere for 16 h. Upon completion, the mixture was diluted with _H2O (50 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (2 x 30 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuum to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA) to give the title compound (4.90 g, 37% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 6.0 Hz, 2H), 6.82 (d, J = 6.0 Hz, 2H), 4.18 (d, J = 4.0 Hz, 2H), 3.87 (d, J = 6.4 Hz, 2H), 2.80 - 2.74 (m, 2H), 2.09 - 1.90 (m, 1H), 1.82 (d, J = 12.8 Hz, 2H), 1.48 (s, 9H), 1.35 - 1.23 (m, 2H). LC-MS(ESI ⁺ )m/z 293.3(M+H) ⁺ .

Step 2 4-(4-piperidyloxymethyl)piperidine-1-carboxylate tert-butyl

A mixture of tert-butyl 4-(4-pyridyloxymethyl)piperidine-1-carboxylate (2.8 g, 9.58 mmol), PtO ₂ (2.17 g, 9.58 mmol), and HOAc (10.50 g, 174.85 mmol, 10 mL) in EtOH (28 mL) was degassed and purged with H ₂ three times. This mixture was then stirred at 40 °C under an atmosphere of H ₂ for 16 h. Upon completion, the mixture was filtered and concentrated in vacuo to provide the title compound (2.5 g, 73% yield, HOAc salt) as a white oil. ^1H NMR (400 MHz, _CDCl3 ) δ 4.12 (d, J = 2.0 Hz, 2H), 3.57 (s, 1H), 3.28 - 3.18 (m, 3H), 3.13 - 3.05 (m, 2H), 3.03 - 2.92 (m, 1H), 2.73 - 2.69 (m, 2H), 2.05 (s, 9H), 2.00 (s, 1H), 1.89 - 1.79 (m, 2H), 1.77 - 1.63 (m, 4H), 1.31 - 1.24 (m, 1H), 1.20 - 1.09 (m, 2H).

Step 3 4-[(1-benzyloxycarbonyl-4-piperidyl)oxymethyl]piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(4-piperidyloxymethyl)piperidine-1-carboxylate (2.60 g, 7.25 mmol, HOAC) in DCM (30 mL) was added TEA (1.47 g, 14.5 mmol, 2.02 mL) and CbzCl (990 mg, 5.80 mmol, 825 uL, CAS#501-53-1). The mixture was stirred at 25° C. for 3 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 60%-85%, 22 min) to give the title compound (760 mg, 24% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.39 - 7.34 (m, 4H), 7.34 - 7.29 (m, 1H), 5.13 (s, 2H), 4.11 (d, J = 13.2 Hz, 2H), 3.79 (s, 2H), 3.47 - 3.41 (m, 1H), 3.30 - 3.22 (m, 4H), 2.75 - 2.65 (m, 2H), 1.80 (s, 2H), 1.72 (dd, J = 3.2, 8.8 Hz, 3H), 1.60 - 1.56 (m, 2H), 1.46 (s, 9H), 1.19 - 1.08 (m, 2H). LC-MS(ESI ⁺ )m/z 433.1(M+H) ⁺ .

Step 4 4-(4-piperidylmethoxy)piperidine-1-carboxylate benzyl

To a solution of tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)oxymethyl]piperidine-1-carboxylate (650 mg, 1.50 mmol) in DCM (3 mL) was added TFA (4.62 g, 40.5 mmol, 3 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (600 mg, 90% yield, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 333.1 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[4-(4-piperidyloxymethyl)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate IT)

Step 1 - 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]methoxy]piperidine-1-carboxylate benzyl

A mixture of benzyl 4-(4-piperidylmethoxy)piperidine-1-carboxylate (250 mg, 752 umol, Intermediate IS), 4-bromo-3-methyl-1H-benzimidazol-2-one (239 mg, 1.05 mmol, synthesized by steps 1-3 of Intermediate H), Cs ₂ CO ₃ (1.47 g, 4.51 mmol), and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (64.7 mg, 75.2 umol) in dioxane (3 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 12 h. Upon completion, the mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 70%-80%, 23 min) to give the title compound (170 mg, 24% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 9.29 (s, 1H), 7.41 - 7.29 (m, 5H), 7.02 - 6.96 (m, 1H), 6.87 (dd, J = 8.0, 12.0 Hz, 2H), 5.14 (s, 2H), 3.78 (s, 2H), 3.75 (s, 3H), 3.53 - 3.45 (m, 1H), 3.38 (d, J = 4.8 Hz, 2H), 3.31 - 3.24 (m, 2H), 3.20 (d, J = 10.0 Hz, 2H), 2.79 - 2.67 (m, 2H), 1.88 (d, J = 12.0 Hz, 5H), 1.74 - 1.59 (m, 2H), 1.51 - 1.39 (m, 2H). LC-MS(ESI ⁺ )m/z 479.4(M+H) ⁺ .

Step 2 - 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methoxy]piperidine-1-carboxylate benzyl

To a solution of benzyl 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]methoxy]piperidine-1-carboxylate (70 mg, 146 umol) in THF (1 mL) was added t-BuOK (29.5 mg, 263 umol) and [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (72.5 mg, 190 umol, intermediate G). The mixture was stirred at -10°C for 12 h. Upon completion, the mixture was quenched with NH ₄ Cl (1 mL), diluted with H ₂ O (8 mL) and extracted with EA (2 x 5 mL). The combined organic layers were washed with brine (2×3 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (100 mg, 97% yield) as a green semi-solid: LC-MS (ESI ⁺ ) m/z 710.4 (M+H) ⁺ .

Step 3 - 3-[3-methyl-2-oxo-4-[4-(4-piperidyloxymethyl)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of benzyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methoxy]piperidine-1-carboxylate (100 mg, 141 umol) in TFA (1 mL) was added TfOH (21.1 mg, 141 umol, 12.5 uL). The mixture was stirred at 70° C. for 2 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 10 min) to give the title compound (20 mg, 32% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 456.2 (M+H) ⁺ .

tert-Butyl N-[2-(4-piperidylmethoxy)ethyl]carbamate (Intermediate IU)

Step 1 - 4-[2-(tert-butoxycarbonylamino)ethoxymethyl]piperidine-1-carboxylate benzyl

A mixture of benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.00 g, 8.02 mmol, CAS# 122860-33-7), NaH (641 mg, 16.0 mmol) in DMF (10 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 25 °C under _N2 atmosphere for 0.5 h, then tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (3.94 g, 17.6 mmol, CAS# 459817-82-4) was added to the mixture. The mixture was stirred at 25 °C under _N2 for 2.5 h. Upon completion, the reaction mixture was quenched with _H2O (10 mL) at 25 °C, then extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 3/1) to give the title compound (1.20 g, yield 38.1%) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.40 - 7.26 (m, 5H) 6.74 (d, J = 5.2 Hz, 1H) 5.06 (s, 2H) 4.00 (d, J = 13.2 Hz, 2H) 3.37 - 3.30 (m, 3H) 3.22 (d, J = 6.4 Hz, 2H) 3.06 (d, J = 6.0 Hz, 2H) 2.81 - 2.75 (m, 1H) 1.69 (s, 1H) 1.64 (d, J = 12.8 Hz, 2H) 1.37 (s, 9H) 1.09 - 0.99 (m, 2H).

Step 2 - tert-butyl N-[2-(4-piperidylmethoxy)ethyl]carbamate

To a solution of benzyl 4-[2-(tert-butoxycarbonylamino)ethoxymethyl]piperidine-1-carboxylate (1.20 g, 3.06 mmol) in MeOH (2 mL) was added Pd/C (361 mg, 305 umol) under _N2 atmosphere. The suspension was degassed and purged with _H2 three times. The mixture was stirred under _H2 at 25 °C for 12 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (780 mg, 99% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) 4.86 (s, 1H) 3.46 (d, J = 4.8Hz, 3H) 3.34 - 3.22 (m, 4H) 3.09 (d, J = 12.4Hz, 1H) 2.61 (d, J = 1.6Hz, 1H) 1.99 - 1.77 (m, 1H) 1.74 - 1.69 (m, 4H) 1.45 (s, 9H) 1.30 - 1.11 (m, 2H).

1-[4-[4-(2-aminoethoxymethyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate IV)

Step 1 - tert-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethyl]carbamate and tert-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-pyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethyl]carbamate

A mixture of 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (607 mg, 1.56 mmol, Intermediate DS), tert-butyl N-[2-(4-piperidylmethoxy)ethyl]carbamate (310 mg, 1.20 mmol, Intermediate IU), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (116 mg, 119 umol), Cs ₂ CO ₃ (781 mg, 2.40 mmol) and 4A molecular sieves (2.00 mg) in dioxane (5 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18 150×25 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 40%-70%, 8 min) to give the crude product as a mixture of the title compounds (260 mg, 38% yield) as a white solid. LC-MS (ESI ⁺ ) m/z (565.4 and 567.4) (M+H) ⁺ .

Step 2 - tert-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-pyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethyl]carbamate (260 mg, 460 umol) in THF (2 mL) was added Pd/C (542 mg, 460 umol) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 three times. The mixture was stirred under _H2 at 25 °C for 16 h. Upon completion, the reaction mixture was filtered and concentrated in reduced pressure to provide a residue. The residue was then purified by prep-HPLC (column: Welch Ultimate C18 150×25 mm×5 um; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (200 mg, 74% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 567.3 (M+H) ⁺ .

Step 3 - 1-[4-[4-(2-aminoethoxymethyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethyl]carbamate (200 mg, 352 umol) in TFA (2 mL) was added TfOH (680 mg, 4.53 mmol). The mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (122 mg, quantitative yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 346.9 (M+H) ⁺ .

tert-Butyl N-[2-[2-(4-piperidylmethoxy)ethoxy]ethyl]carbamate (Intermediate IW)

Step 1 - Benzyl 4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylate

To a solution of ethyl 2-diazoacetate (1.37 g, 12.0 mmol) and benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (1 g, 4.01 mmol, CAS#122860-33-7) in DCM (10 mL) was added Rh ₂ (OAc) ₄ (178 mg, 401 umol). The mixture was stirred at 25° C. for 16 h. Upon completion, the mixture was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=100/1-8/1) to give the crude product. The crude product was purified by reverse phase (0.1% FA) to give the title compound (1.00 g, 64% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.40 - 7.28 (m, 5H), 5.06 (s, 2H), 4.13 - 4.07 (m, 2H), 3.99 (d, J = 13.2 Hz, 2H), 3.31 (d, J = 6.4 Hz, 2H), 2.79 (s, 2H), 1.80 - 1.70 (m, 1H), 1.66 (d, J = 13.6 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.10 - 1.00 (m, 2H).

Step 2 - Benzyl 4-(2-hydroxyethoxymethyl)piperidine-1-carboxylate

To a mixture of benzyl 4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylate (900 mg, 2.68 mmol) in THF (10 mL) and LiAlH ₄ (153 mg, 4.03 mmol) was added the mixture at 0° C. After 10 min, the cooling bath was removed and after stirring at 25° C. for 20 min., the mixture was then stirred at 25° C. under N ₂ atmosphere for 2 h. Upon completion, the mixture was quenched with H ₂ O (1 mL) at 0° C. and then diluted with a solution of 15% NaOH (1 mL). The mixture was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuum to give the residue (800 mg, 87% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.41 - 7.28 (m, 5H), 5.06 (s, 2H), 4.60 - 4.46 (m, 1H), 4.00 (d, J = 13.2 Hz, 2H), 3.48 (d, J = 4.4 Hz, 1H), 3.40 - 3.34 (m, 2H), 3.33 (s, 1H), 3.24 (d, J = 6.4 Hz, 2H), 2.87 - 2.67 (m, 2H), 1.77 - 1.69 (m, 1H), 1.66 (d, J = 12.8 Hz, 2H), 1.10 - 1.02 (m, 2H).

Step 3 - 4-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxymethyl]piperidine-1-carboxylate benzyl

To a solution of benzyl 4-(2-hydroxyethoxymethyl)piperidine-1-carboxylate (800 mg, 2.73 mmol) and tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (1.03 g, 4.64 mmol, CAS#459817-82-4) in THF (8 mL) was added NaH (219 mg, 5.45 mmol, 60% dispersion in mineral oil). The mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was quenched with H ₂ O (1 mL) at 0 °C, then diluted with H ₂ O (10 mL) and extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 55%-75%, 28 min) to give the title compound (300 mg, 26% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.38 - 7.35 (m, 4H), 7.32 (dd, J = 4.0, 4.8 Hz, 1H), 7.27 (s, 1H), 5.13 (s, 2H), 4.20 (d, J = 7.2 Hz, 2H), 3.61 - 3.53 (m, 6H), 3.32 (d, J = 6.0 Hz, 4H), 2.83 - 2.74 (m, 2H), 1.80 (dd, J = 6.8, 3.6 Hz, 1H), 1.75 (d, J = 13.2 Hz, 2H), 1.45 (s, 9H), 1.21 - 1.10 (m, 2H). LC-MS(ESI ⁺ )m/z 437.4(M+H) ⁺ .

Step 4 - tert-butyl N-[2-[2-(4-piperidylmethoxy)ethoxy]ethyl]carbamate

To a solution of benzyl 4-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxymethyl]piperidine-1-carboxylate (300 mg, 687 umol) in MeOH (3 mL) was added Pd/C (407 mg, 344 umol, 10 wt%) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 several times. The mixture was stirred under _H2 (15 psi) at 25 °C for 12 h. Upon completion, the mixture was filtered and concentrated under reduced pressure to give the title compound (200 mg, 96% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 5.07 - 4.89 (m, 1H), 3.64 - 3.59 (m, 2H), 3.58 - 3.54 (m, 4H), 3.36 - 3.30 (m, 4H), 3.09 (dd, J = 12.4, 2.8 Hz, 1H), 2.76 - 2.58 (m, 1H), 1.99 - 1.84 (m, 1H), 1.76 - 1.71 (m, 2H), 1.61 (d, J = 2.0 Hz, 2H), 1.45 (s, 9H), 1.34 - 1.22 (m, 1H), 1.22 - 1.08 (m, 2H).

1-[4-[4-[2-(2-aminoethoxy)ethoxymethyl]-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate IX)

Step 1 - tert-butyl N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethyl]carbamate and tert-butyl N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-pyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-(4-piperidylmethoxy)ethoxy]ethyl]carbamate (150 mg, 496 umol, Intermediate IW), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (232 mg, 595 umol, Intermediate DS), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (42.7 mg, 49.6 umol), and Cs ₂ CO ₃ (323 mg, 992 umol) in dioxane (1 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 12 h. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 250×50 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 41%-71%, 8 min) to give the crude product as a mixture of the title compounds (140 mg, 47% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z (609.4 and 611.3) (M+H) ⁺ .

Step 2 - N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-pyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethyl]carbamate (140 mg, 230 umol) in THF (1 mL) was added Pd/C (272 mg, 10 wt%) under _N2 . The suspension was degassed under reduced pressure and purged with _H2 several times. The mixture was stirred under _H2 (15 psi) at 25 °C for 12 h. Upon completion, the mixture was filtered and concentrated in reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (TFA)-ACN]; B%: 22%-52%, 10 min) to give the title compound (80.0 mg, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 611.4 (M+H) ⁺ .

Step 3 - 1-[4-[4-[2-(2-aminoethoxy)ethoxymethyl]-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]methoxy]ethoxy]ethyl]carbamate (80 mg, 131 umol) in TFA (1 mL) was added TfOH (20 mg, 131 umol, 12.0 uL). The mixture was stirred at 70° C. for 2 hours. Upon completion, the mixture was concentrated in vacuo to give the title compound (51 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 391.1 (M+H) ⁺ .

4-[[6-(cyclohexoxy)-9H-purin-2-yl]amino]-N,3-dimethyl-benzenesulfonamide (Intermediate IY)

Step 1 - 2-chloro-6-(cyclohexoxy)-9H-purine

To a solution of cyclohexanol (1.06 g, 10.5 mmol) in DMF (30 mL) was added NaH (846 mg, 21.1 mmol, 60% dispersion in mineral oil) at 0° C. The reaction was stirred at 0° C. for 0.5 h. 2,6-Dichloro-9H-purine (2.00 g, 10.58 mmol, CAS#5451-40-1) was then added and the mixture was stirred at 25° C. for 16 h. Upon completion, the reaction was quenched with water (2 mL) at 0° C. The mixture was diluted with EA (100 mL) and washed with water (70 mL). The aqueous phase was then filtered. The filter cake was dried in vacuum to give the title compound (1.56 g, 58% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 252.8 (M+H) ⁺ .

Step 2 - 2-chloro-6-(cyclohexoxy)-9-tetrahydropyran-2-yl-purine

A mixture of 2-chloro-6-(cyclohexoxy)-9H-purine (1.56 g, 6.17 mmol), DHP (1.04 g, 12.3 mmol) and TsOH (106 mg, 617 umol) in THF (22 mL) was stirred at 70° C. for 16 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (100 mL×3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (1.6 g, 76% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.61 (s, 1H), 5.74 - 5.60 (m, 1H), 5.37 - 5.24 (m, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.83 - 3.63 (m, 1H), 2.30 - 2.18 (m, 1H), 2.08 - 1.91 (m, 4H), 1.81 - 1.69 (m, 3H), 1.64 - 1.52 (m, 5H), 1.49 - 1.37 (m, 2H), 1.36 - 1.25 (m, 1H).

Step 3 - N-(4-benzylsulfanyl-2-methyl-phenyl)-6-(cyclohexoxy)-9-tetrahydropyran-2-yl-purine-2-amine

A solution of 2-chloro-6-(cyclohexoxy)-9-tetrahydropyran-2-yl-purine (1.60 g, 4.75 mmol), 4-benzylsulfanyl-2-methyl-aniline (980 mg, 4.28 mmol, intermediate DE), Pd(OAc) ₂ (106 mg, 475 umol), BINAP (295 mg, 475 umol) and _Cs2CO3 (4.64 _g , 14.2 mmol) in toluene (25 mL) was stirred at 100 _° C under _N2 for 4 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (100 mL x 2), dried over _Na2SO4 and filtered. The filtrate was concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (1.6 g, 63% yield) as a red solid: LC-MS (ESI ⁺ ) m/z 530.1 (M+H) ⁺ .

Step 4 - 4-[[6-(cyclohexoxy)-9H-purin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-6-(cyclohexoxy)-9-tetrahydropyran-2-yl-purin-2-amine (100 mg, 188 umol), H ₂ O (34.0 ug, 1.89 umol) in HOAc (0.3 mL) and ACN (0.9 mL) was added NCS (75.6 mg, 566 umol). The reaction was stirred at 25° C. in the dark for 1 h. Upon completion, the reaction was concentrated in vacuo to give the title compound (79.0 mg, 187 umol, 99% yield) as a green oil. LC-MS (ESI ⁺ ) m/z 422.2 (M+H) ⁺ .

Step 5 - 4-[[6-(cyclohexoxy)-9H-purin-2-yl]amino]-N,3-dimethyl-benzenesulfonamide

To a solution of methanamine; hydrochloride (18.9 mg, 280 umol) and TEA (94.7 mg, 936 umol) in DCM (2 mL) was added 4-[[6-(cyclohexoxy)-9H-purin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (79.0 mg, 187 umol) at 0° C. The reaction was then stirred at 25° C. for 1 h. Upon completion, the reaction was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters xbridge 150×25 mm 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 26%-56%, 8 min) to give the title compound (14.0 mg, 18% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.92 - 12.66 (m, 1H), 8.54 (s, 1H), 8.15 - 7.92 (m, 2H), 7.64 - 7.50 (m, 2H), 7.27 (q, J = 5.2 Hz, 1H), 5.33 - 5.17 (m, 1H), 2.41 (d, J = 5.2 Hz, 3H), 2.36 (s, 3H), 2.11 - 2.00 (m, 2H), 1.81 - 1.75 (m, 2H), 1.62 - 1.49 (m, 3H), 1.46 - 1.20 (m, 3H); LC-MS(ESI ⁺ )m/z 417.0(M+H) ⁺ .

3-Methyl-4-[[4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonyl chloride (Intermediate IZ)

Step 1 - N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1 g, 4.61 mmol, CAS#3932-97-6) in a mixed solvent of t-BuOH (30 mL) and DCE (30 mL) was added ZnCl ₂ (1 M, 5.53 mL) at 0° C. After 1 h, a solution of 4-benzylsulfanyl-2-methyl-aniline (1.06 g, 4.61 mmol, intermediate DE) and TEA (513 mg, 5.07 mmol) in a mixed solvent of t-BuOH (15 mL) and DCE (15 mL) was added dropwise to the above solution. The mixture was stirred at 25° C. for 16 h. On completion, the mixture was quenched with ice water (100 ml) and extracted with DCM (90 ml×3). The combined organic phase was washed with H ₂ O (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=30/1 to 15/1) to give the title compound (1.7 g, 81% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.65 (s, 1H), 7.40 - 7.34 (m, 2H), 7.33 - 7.27 (m, 3H), 7.26 - 7.19 (m, 3H), 4.24 (s, 2H), 2.15 (s, 3H); LC-MS(ESI ⁺ )m/z 409.8(M+H) ⁺ .

Step 2 - N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl) _pyrimidin -2-amine (0.8 g, 1.95 mmol), (1-methylpyrazol-4-yl)boronic _{acid (491 mg, 3.90 mmol, CAS#847818-55-7), Pd(PPh3)2Cl2 ( 137} mg, 195 umol) and _Na2CO3 (2M, 2.73 mL) in dioxane (23 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100 °C under _N2 atmosphere for 12 h. Upon completion, the mixture was quenched with ice water (100 ml) and extracted with DCM (50 ml x 3). The combined organic phase was washed with H ₂ O (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (SiO ₂ , PE/EA=20/1 to 1/1) to give the title compound (0.8 g, yield 83%) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.43 (s, 1H), 8.62 (s, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.42 - 7.35 (m, 3H), 7.33 - 7.27 (m, 2H), 7.26 - 7.17 (m, 3H), 4.23 (s, 2H), 3.92 (s, 3H), 2.18 (s, 3H); LC-MS(ESI ⁺ ) m/z 456.3(M+H) ⁺ .

Step 3 - 3-Methyl-4-[[4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonyl chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 219 umol) in HOAc (0.4 mL) and ACN (1.2 mL) was added NCS (87.9 mg, 658 umol). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated to give the title compound (100 mg, 92% yield, HOAc) as a yellow oil. LC-MS (ESI ⁺ ) m/z 431.9 (M+H) ⁺ .

4-[[4-Cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate JA)

Step 1 - N-(4-benzylsulfanyl-2-methyl-phenyl)-4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-amine

To a 40 mL vial equipped with a stir bar was added N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (500 mg, 1.22 mmol, intermediate EA ₎ , bromocyclohexane (258 mg, 1.59 mmol), TTMSS (303 mg, 1.22 mmol), NiCl.dtbbpy (7.28 mg, 18.3 umol), Ir[dF( _CF )ppy] ₍ dtbpy)( _PF ) (13.6 mg, 12.2 umol), and _NaCO ( ₂₅₈ mg, 2.44 mmol) in DME (10 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 10 W blue LED lamp (3 cm away) for 14 h while maintaining the reaction temperature at 25° C. with cooling water. Upon completion, the reaction mixture was concentrated in vacuum. The mixture was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with saturated NaCl in H ₂ O (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=50:1-30:1) and reverse phase (0.1% FA condition) to give the title compound (215 mg, 38% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.40 (s, 1H), 8.53 (s, 1H), 7.37 - 7.33 (m, 2H), 7.32 - 7.26 (m, 2H), 7.26 - 7.19 (m, 2H), 7.15 (dd, J = 2.0, 8.4 Hz, 1H), 4.22 (s, 2H), 3.30 (s, 1H), 2.74 - 2.71 (m, 1H), 2.16 (s, 3H), 1.78 - 1.75 (m, 2H), 1.70 - 1.65 (m, 3H), 1.62 - 1.48 (m, 2H), 1.37 - 1.13 (m, 3H). LC-MS(ESI ⁺ )m/z 458.1(M+H) ⁺ .

Step 2 - 4-[[4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-amine (60 mg, 131 umol) in HOAc (0.5 mL) and ACN (1.5 mL) was added NCS (52.5 mg, 393 umol). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (60 mg, 98% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 434.1 (M+H) ⁺ .

4-[2-(4-piperidyl)ethyl]piperazine-1-carboxylate benzyl (Intermediate JB)

Step 1 - 4-[2-(1-benzyloxycarbonyl-4-piperidyl)ethyl]piperazine-1-carboxylate tert-butyl

To a solution of benzyl piperazine-1-carboxylate (1.02 g, 4.62 mmol, 893 uL, CAS#31166-44-6) in THF (10 mL), KOAc (4.32 g, 44.0 mmol) was added dropwise, followed by tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g, 4.40 mmol, CAS#142374-19-4) at 0° C. After addition, the mixture was stirred at this temperature for 30 min, then NaBH(OAc) ₃ (1.86 g, 8.80 mmol) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 1.5 h. Upon completion, the mixture was diluted with H ₂ O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 5/1) to give the title compound (2.0 g, 88% yield, HOAc salt) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.38 - 7.31 (m, 5H), 5.13 (s, 2H), 4.08 (d, J = 12.0 Hz, 2H), 3.59 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 12.0 Hz, 2H), 2.58 - 2.48 (m, 6H), 1.63 (d, J = 12.4 Hz, 2H), 1.47 (s, 3H), 1.45 (s, 9H), 1.17 - 1.05 (m, 2H). LC-MS(ESI ⁺ )m/z 432.5(M+H) ⁺ .

Step 2 - 4-[2-(4-piperidyl)ethyl]piperazine-1-carboxylate benzyl

To a solution of benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)ethyl]piperazine-1-carboxylate (2 g, 4.07 mmol, HOAc) in DCM (10 mL) was added TFA (13.5 g, 119 mmol, 8.80 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (1.8 g, 99% yield, TFA salt) as a white solid. LC-MS (ESI ⁺ ) m/z 332.4 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[4-(2-piperazin-1-ylethyl)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JC)

Step 1 - 4-[2-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]ethyl]piperazine-1-carboxylate benzyl

A mixture of benzyl 4-[2-(4-piperidyl)ethyl]piperazine-1-carboxylate (100 mg, 225 umol, TFA, Intermediate JB), 4-bromo-3-methyl-1H-benzimidazol-2-one (51.0 mg, 225 umol, synthesized by steps 1-3 of Intermediate H), Cs ₂ CO ₃ (439 mg, 1.35 mmol, 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (9.66 mg, 11.2 umol, CAS# 1435347-24-2) in dioxane (4 mL) was degassed and purged with N ₂ three times. This mixture was then heated at 110 °C with N The mixture was stirred under ₂ atmosphere for 12 hours. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250 x 50 mm x 15 um; mobile phase: [water (FA)-ACN]; B%: 20%-60%, 25 min) to give the title compound (50 mg, 43% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.04 (s, 1H), 7.32 - 7.12 (m, 5H), 6.81 - 6.74 (m, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.60 (dd, J = 0.8, 7.6 Hz, 1H), 4.96 (s, 2H), 3.43 (s, 3H), 3.31 (s, 4H), 2.94 (d, J = 11.2 Hz, 2H), 2.41 - 2.36 (m, 2H), 2.36 - 2.27 (m, 6H), 1.62 ( d, J = 10.0 Hz, 2H), 1.36 - 1.23 (m, 4H). LC-MS(ESI ⁺ )m/z 478.2(M+H) ⁺ .

Step 2 - 4-[2-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]ethyl]benzyl piperazine-1-carboxylate

To a solution of benzyl 4-[2-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]ethyl]piperazine-1-carboxylate (300 mg, 628 umol) in THF (5 mL) was added t-BuOK (127 mg, 1.13 mmol). After addition, the mixture was stirred at this temperature for 30 min, then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (431 mg, 1.13 mmol, intermediate G) was added dropwise at −10° C. The mixture was then stirred at −10° C. for 12 h. Upon completion, the mixture was quenched with NH ₄ Cl (1 mL), diluted with H ₂ O (8 mL) and extracted with EA (2×5 mL). The organic layer was then washed with brine (2×3 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a residue. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (350 mg, 77% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 - 7.28 (m, 5H), 7.21 (d, J = 8.8 Hz, 2H), 6.95 - 6.89 (m, 2H), 6.89 - 6.84 (m, 2H), 6.76 (s, 1H), 5.50 (dd, J = 5.2, 12.8 Hz, 1H), 5.08 (s, 2H), 4.88 - 4.73 (m, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 3.40 (s, 4H), 3.08 (d, J = 11.6 Hz, 2H), 2.86 - 2.75 (m, 2H), 2.74 - 2.62 (m, 4H), 2.35 (d, J = 4.0 Hz, 6H), 2.08 - 1.98 (m, 1H), 1.77 (d, J = 10.4 Hz, 2H), 1.50 - 1.37 (m, 4H). LC-MS(ESI ⁺ )m/z 709.4(M+H) ⁺ .

Step 3 - 3-[3-methyl-2-oxo-4-[4-(2-piperazin-1-ylethyl)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of benzyl 4-[2-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]ethyl]piperazine-1-carboxylate (350 mg, 494 umol) in TFA (2 mL) was added TfOH (578 mg, 3.85 mmol, 0.34 mL). The mixture was stirred at 70° C. for 2 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (224 mg, 99% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 455.0.0 (M+H) ⁺ .

N-[2-(2-aminoethoxy)ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide (Intermediate JD)

Step 1 - N-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (112 mg, 551 umol, CAS# 127828-22-2) in DCM (3 mL) was added TEA (1.65 mmol, 230 uL) and 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (250 mg, 551 umol, Intermediate CW), then the mixture was stirred at 25° C. for 1 hour. Upon completion, the mixture was filtered to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (column: Phenomenex C18 150 x 25 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 42% to 72%, 8 min) to give the title compound (150 mg, 43% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.75 (s, 1H), 8.17 (s, 1H), 7.74 - 7.68 (m, 2H), 7.66 - 7.59 (m, 2H), 6.85 - 6.75 (m, 1H), 5.80 - 5.67 (m, 1H), 3.35 (t, J = 5.6 Hz, 2H), 3.28-3.24 (m, 3H), 3.07 - 3.01 (m, 2H), 2.95 - 2.89 (m, 2H), 2.32 (s, 3H), 2.18 - 2.04 (m, 2H), 1.76 - 1.63 (m, 4H), 1.50 - 1.42 (m, 2H), 1.36 (s, 9H). LC-MS(ESI ⁺ )m/z 620.8(M+H) ⁺ .

Step 2 - N-[2-(2-aminoethoxy)ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide

To a solution of tert-butyl N-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]ethyl]carbamate (140 mg, 225 umol) was added HCl/dioxane (4 mL) and the mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (123 mg, 97% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 520.8 (M+H) ⁺ .

2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-phenoxy]acetic acid (Intermediate JE)

Step 1 - 2-(4-methyl-3-nitro-phenoxy) methyl acetate

To a solution of 4-methyl-3-nitro-phenol (5 g, 30 mmol, CAS#2042-14-0) in acetone (100 mL) was added 2-bromoacetate methyl (7.49 g, 50 mmol, 4.62 mL) and Cs ₂ CO ₃ (21.28 g, 65.30 mmol) and the mixture was then heated to 60° C. for 16 h. Upon completion, the reaction was cooled to 20° C. and then poured into water (700 mL), during which time a solid precipitated. The mixture was filtered and the filter cake was washed with water (100 ml) and then dried in vacuo to give the title compound (5 g, 6% yield) as a grey solid.

Step 2 - 2-(3-amino-4-methyl-phenoxy) methyl acetate

To a solution of methyl 2-(4-methyl-3-nitro-phenoxy)acetate (5 g, 20 mmol) in MeOH (100 mL) was added Pd/C (0.5 g, 20 mmol, 5 wt%) and the resulting suspension was degassed and then purged with _H2 gas (15 psi). The reaction was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (4 g, 20.49 mmol, 92% yield) as a colorless oil.

Step 3 - 3-[5-(2-methoxy-2-oxo-ethoxy)-2-methyl-anilino]propanoic acid

To a solution of methyl 2-(3-amino-4-methyl-phenoxy)acetate (4 g, 20 mmol) in H ₂ O (2 mL) was added acrylic acid (4.43 g, 61.5 mmol, 4.22 mL) and the mixture was stirred for 3 h at 80° C. Upon completion, the reaction was concentrated in vacuo to give the title compound (14 g) as a yellow gum.

Step 4 - 2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-phenoxy]acetic acid

To a solution of 3-[5-(2-methoxy-2-oxo-ethoxy)-2-methyl-anilino]propanoic acid (13.33 g, 29.93 mmol) in AcOH (30 mL) was added urea (5.39 g, 89.79 mmol, 4.81 mL) and the mixture was heated to 130° C. for 16 h. Upon completion, the reaction was cooled to 20° C., then HCl (60 ml, 2N) was added and the mixture was stirred for 10 min. The resulting mixture was poured into water (70 ml), at which time a solid precipitated. The suspension was filtered and the filter cake was washed with water (20 ml). The filter cake was triturated with MeOH (10 ml) and then filtered. The filter cake was dried in vacuum to give the title compound (1.30 g, 16% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.97 (br s, 1H), 10.33 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.89 (t, J = 6.8 Hz, 1H), 6.81 - 6.78 (m, 1H), 4.64 (s, 2H), 3.79 - 3.73 (m, 1H), 3.51 - 3.46 (m, 1H), 2.81 - 2.60 (m, 2H), 2.01 (s, 3H). LC-MS(ESI+) m/z 279.2(M+H) ⁺ .

2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetic acid (Intermediate JF)

Step 1 - 2-(4-chloro-3-nitro-phenoxy) methyl acetate

To a solution of 4-chloro-3-nitro-phenol (10 g, 60 mmol, CAS#610-78-6) in DMF (100 mL) was added 2-bromoacetate methyl (10.58 g, 69.14 mmol, 6.53 mL, CAS#96-32-2), and K ₂ CO ₃ (15.93 g, 115.2 mmol). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was partitioned between water (50 mL) and EtOAc (35 mL). The organic phase was separated, washed with water (20 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (10 g, 71% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 7.47 - 7.29 (m, 2H), 7.02 (dd, J = 3.0, 8.9 Hz, 1H), 4.62 (s, 2H), 3.75 (s, 3H). LC-MS (ESI+) m/z 215.0 (M-30) ⁺ .

Step 2 - 2-(3-amino-4-chloro-phenoxy) methyl acetate

To a solution of methyl 2-(4-chloro-3-nitro-phenoxy)acetate (10 g, 40 mmol) in MeOH (40 mL) was added iron powder (6.82 g, 122.14 mmol), NH ₄ Cl (10.89 g, 203.6 mmol) and water (130 mL) at 25° C. The mixture was stirred at 60° C. for 4 h. Upon completion, the reaction mixture was partitioned between water (100 mL) and EtOAc (30 mL). The organic phase was separated, washed with water (20 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5:1, R _f =0.6) to give the title compound (8 g, 89% yield) as a yellow solid. ^1H NMR (400 MHz, ) δ = 7.14 (s, 1H), 7.12 (s, 1H), 7.17 - 7.09 (m, 1H), 6.35 (d, J = 2.8 Hz, 1H), 6.25 (dd, J = 2.8, 8.7 Hz, 1H), 4.58 (s, 2H), 4.16 - 4.02 (m, 2H), 3.84 - 3.78 (m, 1H), 3.80 (s, 2H), 2.05 (s, 1H), 1.26 (t, J = 7.2 Hz, 1H). LC-MS(ESI+) m/z 216.0(M+H) ⁺ .

Step 3 - 2-[4-chloro-3-(2,4-dioxohexahydropyrimidin-1-yl)phenoxy]acetic acid

A mixture of methyl 2-(3-amino-4-chloro-phenoxy)acetate (4 g, 19 mmol) and acrylic acid (5.35 g, 74.2 mmol, 5.09 mL) was stirred at 120° C. for 4 h. Then, AcOH (40 mL) and urea (5.57 g, 92.8 mmol, 4.97 mL) were added at 20° C. The resulting mixture was stirred at 120° C. for 12 h. Upon completion, the reaction mixture was poured into a mixture of water (100 mL) and HCl (12 M, 1.55 mL) and the mixture was stirred at 20° C. for 0.5 h. Then, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by Combiflash® (0.1% TFA) to give the title compound (358.67 mg, 6% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 13.34 - 12.83 (m, 1H), 10.46 (s, 1H), 7.50 - 7.41 (m, 1H), 7.14 (d, J = 2.8 Hz, 1H), 6.99 -6.89 (m, 1H), 4.71 (s, 2H), 3.81 - 3.50 (m, 2H), 2.82 - 2.63 (m, 2H). LC-MS(ESI+)m/z 299.0(M+H) ⁺ .

N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide (Intermediate JG)

Step 1 - N-[2-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]carbamate tert-butyl

To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (137 mg, 551 umol, CAS# 153086-78-3) in DCM (4 mL) was added TEA (167 mg, 1.65 mmol) until pH=7-8, followed by 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (250 mg, 551 umol, Intermediate CW). The mixture was then stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 150×25 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 42%-72%, 8 min) to give the title compound (90.0 mg, 24% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.66 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 7.72 - 7.68 (m, 2H), 7.67 - 7.60 (m, 2H), 6.74 (t, J = 5.4 Hz, 1H), 5.79 - 5.68 (m, 1H), 3.47 - 3.38 (m, 7H), 3.09 - 3.02 (m, 2H), 2.92 - 2.87 (m, 2H), 2.32 (s, 3H), 2.17 - 2.03 (m, 2H), 1.69 (s, 4H), 1.45 (s, 3H), 1.35 (s, 9H). LC-MS(ESI ⁺ )m/z 664.8(M+H) ⁺ .

Step 2 - N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide

A solution of tert-butyl N-[2-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]carbamate (70.0 mg, 105 umol) in HCl/dioxane (2 mL) and the mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (62.0 mg, 97% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 565.0 (M+H) ⁺ .

4-Chloro-3-(2,4-dioxohexahydropyrimidin-1-yl)benzoic acid (Intermediate JH)

tert-Butyl N-[3-(4-piperidyl)propyl]carbamate (Intermediate JI)

Step 1 - tert-butyl N-[3-(4-pyridyl)propyl]carbamate

To a solution of 3-(4-pyridyl)propan-1-amine (1.00 g, 7.34 mmol, CAS#30532-36-6) in DCM (10 mL) was added Boc ₂ O (1.92 g, 8.81 mmol) and Et ₃ N (1.49 g, 14.6 mmol). The mixture was stirred at 25° C. for 2 h. Upon completion, the residue was diluted with H ₂ O (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×6 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 1/1) to give the title compound (1.50 g, 85% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.49 (d, J = 6.0 Hz, 2H) 7.12 (d, J = 5.6 Hz, 2H) 4.63 (s, 1H) 3.16 (d, J = 6.4 Hz, 2H) 2.66 - 2.61 (m, 2H) 1.86 - 1.78 (m, 2H) 1.44 (s, 9H). LC-MS(ESI ⁺ ) m/z 237.1(M+H) ⁺ .

Step 2 - tert-butyl N-[3-(4-piperidyl)propyl]carbamate

To a solution of tert-butyl N-[3-(4-pyridyl)propyl]carbamate (1.50 g, 6.35 mmol) in EtOH (12 mL) was added PtO ₂ (1.44 g, 6.35 mmol) and AcOH (6.30 g, 104 mmol) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ three times. The mixture was stirred under H ₂ at 40 °C for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.50 g, 98% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 3.37 (d, J = 12.8 Hz, 2 H) 3.09 (d, J = 5.2 Hz, 2 H) 2.81 (t, J = 12.4 Hz, 2 H) 1.82 (d, J = 11.6 Hz, 2 H) 1.69 - 1.56 (m, 1 H) 1.52 - 1.46 (m, 5 H) 1.43 (s, 9 H) 1.31 (d, J = 5.6 Hz, 2 H) 1.28 - 1.22 (m, 1 H).

1-[4-[4-(3-aminopropyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate JJ)

Step 1 - tert-butyl N-[3-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]propyl]carbamate

A mixture of tert-butyl N-[3-(4-piperidyl)propyl]carbamate (233 mg, 963 umol, Intermediate JI), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (150 mg, 385 umol, Intermediate DS), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (37.4 mg, 38.5 umol), and Cs ₂ CO ₃ (502 mg, 1.54 mmol) in dioxane (3 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18 150×25 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 46%-76%, 8 min) to give the title compound (130 mg, 60% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.43 (d, J = 8.8 Hz, 2H) 7.12 (d, J = 8.8 Hz, 2H) 6.92 (d, J = 8.8 Hz, 2H) 6.83 (d, J = 8.4 Hz, 2H) 4.95 (s, 2H) 3.79 (s, 3H) 3.72 (t, J = 6.8 Hz, 2H) 3.65 (d, J = 12.4 Hz, 2H) 3.17 - 3.08 (m, 2H) 2.85 (t, J = 6.8 Hz, 2H) 2.74 - 2.64 (m, 2H) 1.78 (d, J = 11.2 Hz, 2H) 1.51 (d, J = 7.6 Hz, 3 H) 1.46 (s, 9 H) 1.35 (d, J = 12.0 Hz, 2 H) 1.33 - 1.26 (m, 3 H). LC-MS(ESI ⁺ )m/z 551.0(M+H) ⁺ .

Step 2 - 1-[4-[4-(3-aminopropyl)-1-piperidyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[3-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidyl]propyl]carbamate (70.0 mg, 127 umol) in TFA (1 mL) was added TfOH (340 mg, 2.27 mmol). The mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the title compound (42.0 mg, 100% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 330.9 (M+H) ⁺ .

3-[3-Methyl-4-[4-(methylaminomethyl)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JK)

Step 1 - tert-butyl N-methyl-N-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]methyl]carbamate

A mixture of 4-bromo-3-methyl-1H-benzimidazol-2-one (0.85 g, 3.74 mmol, synthesized by steps 1-3 of intermediate H), tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate (940 mg, 4.12 mmol, CAS#138022-04-5), RuPhos (174 mg, 374 umol), _Pd2 (dba) ₃ (342 mg, 374 umol) and t-BuOK (1.26 g, 11.2 mmol) in dioxane (20 mL) was stirred at 90 °C under _{N2 for} 16 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (70 mL x 3), dried over _Na2SO4 and filtered. The filtrate was concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , DCM/ethyl acetate=0% to 35%) to give the title compound (800 mg, 57% yield) as a brown solid: LC-MS (ESI ⁺ ) m/z 375.3 (M+H) ⁺ .

Step 2 - N-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-N-methyl-carbamic acid tert-butyl

To a solution of tert-butyl N-methyl-N-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]methyl]carbamate (460 mg, 1.23 mmol) in THF (10 mL) was added t-BuOK (413 mg, 3.69 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. Then, [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (702 mg, 1.84 mmol, intermediate G) was added to the above mixture at 0 °C. The reaction was stirred at 25 °C for 1.5 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (100 mL x 2) and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , DCM/ethyl acetate=100/0 to 50/50) to give the title compound (400 mg, 53% yield) as a brown solid: LC-MS (ESI ⁺ ) m/z 606.4 (M+H) ⁺ .

Step 3 - 3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl N-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-N-methyl-carbamate (270 mg, 445 umol) and TfOH (1.38 g, 9.18 mmol) in TFA (1 mL) was stirred at 70° C. for 1 h. Upon completion, the reaction was concentrated in vacuo to afford the title compound (222 mg, 99% yield, TFA) as a brown oil. LC-MS (ESI ⁺ ) m/z 386.0 (M+H) ⁺ .

Step 4 - N-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-N-methyl-carbamic acid tert-butyl

To a mixture of 3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (222 mg, 444 umol, TFA) and TEA (134 mg, 1.33 mmol) in DCM (2 mL) was added Boc ₂ O (145 mg, 666 umol). The reaction was stirred at 25 °C for 1 h. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (70 mL x 2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuum. The crude product was triturated with PE:EA = 10:1 (10 mL) at 25 °C for 30 min to give the title compound (200 mg, 92% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 486.4 (M+H) ⁺ .

Step 5 - 3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl N-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-N-methyl-carbamate (200 mg, 411 umol) and TFA (770 mg, 6.75 mmol, 0.5 mL) in DCM (2 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction was concentrated in vacuo to afford the title compound (205 mg, 99% yield, TFA) as a brown oil. LC-MS (ESI ⁺ ) m/z 386.1 (M+H) ⁺ .

3-[3-Methyl-4-[4-[[methyl(4-piperidyl)amino]methyl]-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JL)

Step 1 - 4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl-methyl-amino]piperidine-1-carboxylate tert-butyl

To a solution of 3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (202 mg, 404 umol, TFA, intermediate CL), TEA (40.9 mg, 404 umol) and HOAc (48.5 mg, 808 umol) in DMF (1 mL) and THF (3 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (241 mg, 1.21 mmol, CAS# 79099-07-3). The reaction was stirred at 25° C. for 0.5 h. NaBH(OAc) ₃ (128 mg, 606 umol) was then added and the mixture was stirred at 40° C. for 1.5 h. Upon completion, the reaction was quenched with water (0.05 mL) and diluted with EA (70 mL). The organic layer was washed with water (70 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 10 min) to give the title compound (130 mg, 56% yield) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.02 - 6.96 (m, 1H), 6.94 - 6.86 (m, 2H), 5.42 - 5.37 (m, 1H), 4.68 (d, J = 3.6 Hz, 2H), 4.17 - 4.02 (m, 2H), 3.63 (s, 3H), 3.15 (d, J = 10.0 Hz, 2H), 2.94 (s, 4H), 2.78 (s, 3H), 2.02 - 1.90 (m, 4H), 1.72 - 1.62 (m, 5H), 1.41 (s, 9H), 1.30 - 1.16 (m, 5H); LC-MS(ESI ⁺ )m/z 569.3(M+H) ⁺ .

Step 2 - 3-[3-methyl-4-[4-[[methyl(4-piperidyl)amino]methyl]-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl 4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl-methyl-amino]piperidine-1-carboxylate (50.0 mg, 87.9 umol) in HCl/dioxane (4 M, 2 mL) was stirred at 25° C. for 1 h. Upon completion, the residue was concentrated in vacuo to give the title compound (44 mg, 99% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 469.2 (M+H) ⁺ .

3-[4-(2,7-Biazhaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JM)

Step 1 - 7-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl

To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.00 g, 8.84 mmol, CAS# 236406-55-6), 4-bromo-3-methyl-1H-benzimidazol-2-one (2.21 g, 9.72 mmol, synthesized by steps 1-3 of intermediate H) in dioxane (20 mL) was added _Cs2CO3 ( _5.76 g, 17.6 mmol), 4A molecular sieves and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (380 mg, 441 umol) and the mixture was purged with _N2 three times. The mixture was then stirred at 110°C under _N2 atmosphere for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue, which was then purified by prep-HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 55%-65%, 22 min) to give the title compound (1.4 g, 41% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.77 (s, 1H), 6.90 - 6.84 (m, 1H), 6.79 - 6.75 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 3.62 (d, J = 2.0 Hz, 2H), 3.52 (s, 3H), 2.95 (d, J = 2.0 Hz, 2H), 2.63 - 2.56 (m, 2H), 1.83 (s, 6H), 1.37 (s, 9H).

Step 2 - 7-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl

To a solution of tert-butyl 7-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (900 mg, 2.42 mmol) in THF (5 mL) was added t-BuOK (488 mg, 4.35 mmol) and stirred for 30 min at −10° C. Then, [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (921 mg, 2.42 mmol, intermediate G) was dissolved in THF (5 mL) and added to the above mixture, which was then stirred for 3 h at −10° C. Upon completion, the reaction mixture was quenched with NH ₄ Cl (10 mL) at 25° C., then diluted with H ₂ O (50 mL) and extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 49%-79%, 22 min) to give the title compound (647 mg, 44% yield) as a grey solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.19 (d, J = 8.8 Hz, 2H), 6.92 - 6.82 (m, 4H), 6.76 (s, 1H), 5.50 - 5.45 (m, 1H), 4.86 - 4.69 (m, 2H), 3.71 (s, 3H), 3.66 (s, 2H), 3.60 (s, 3H), 3.58 - 3.52 (m, 2H), 3.02 - 2.95 (m, 2H), 2.81 - 2.80 (m, 1H), 2.75 (s, 1H), 2.69 - 2.61 (m, 2H), 2.05 - 1.98 (m, 1H), 1.85 (s, 4H), 1.38 (s, 9H).

Step 3 - 3-[4-(2,7-biazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 7-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 331 umol) in TFA (1.2 mL) was added TfOH (340 mg, 2.27 mmol). The mixture was then stirred at 70° C. for 2 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the title compound (160 mg, 97% yield, TFA salt) as a white solid. LC-MS (ESI ⁺ ) m/z 384.1 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[2-(4-piperidyl)-2,7-diazaspiro[3.5]nonan-7-yl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JN)

Step 1 - 5-Bromo-N-cyclopentyl-2-methylsulfanyl-pyrimidin-4-amine

To a solution of 3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (160 mg, 321 umol, TFA salt, intermediate JM) in THF (1 mL) and DMF (0.5 mL) was added AcOK (315 mg, 3.22 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (76.9 mg, 385 umol, CAS# 79099-07-3) at −10° C. for 1 h. NaBH(OAc) ₃ (136 mg, 643 umol) was then added and the mixture was at −10° C. The mixture was then stirred at −10° C. for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (1 mL) at 25° C., then filtered and concentrated in vacuo to give a residue which was then purified by prep-HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 10 min) to give the title compound (90 mg, 49% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.08 (s, 1H), 7.00 - 6.95 (m, 1H), 6.88 - 6.86 (m, 2H), 5.36 - 5.32 (m, 1H), 3.90 (d, J = 12.4 Hz, 2H), 3.62 (s, 4H), 3.49 (d, J = 2.8 Hz, 2H), 3.01 (s, 2H), 2.92 - 2.84 (m, 2H), 2.77 (s, 1H), 2.70 - 2.63 (m, 3H), 2.37 - 2.31 (m, 1H), 2.03 - 1.74 (m, 8H), 1.43 (s, 1H), 1.40 (s, 9H), 1.17 - 1.04 (m, 2H).

Step 2 - 3-[3-methyl-2-oxo-4-[2-(4-piperidyl)-2,7-diazaspiro[3.5]nonan-7-yl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]piperidine-1-carboxylate (50.0 mg, 88.2 umol) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (40 mg, 97% yield, TFA salt) as a red solid. LC-MS (ESI ⁺ ) m/z 467.2 (M+1) ⁺ .

6-Chloro-8-isopropyl-2-[2-methyl-4-[(4-piperazin-1-yl-1-piperidyl)sulfonyl]anilino]pyrido[2,3-d]pyrimidin-7-one (Intermediate JO)

Step 1 - 4-[1-[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonyl-4-piperidyl]piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(4-piperidyl)piperazine-1-carboxylate (69.3 mg, 257 umol, CAS# 205059-24-1) and TEA (118 mg, 1.17 mmol) in DCM (1 mL) was added a solution of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (100 mg, 234 umol, intermediate DG) in DCM (1 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with DCM (20 mL) and washed with H ₂ O (10 mL x 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (150 mg, 97% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.69 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.57 (dd, J = 2.0, 8.4 Hz, 1H), 5.61 (d, J = 3.2 Hz, 1H), 3.68 (d, J = 11.6 Hz, 2H), 3.24 (s, 4H), 2.39 - 2.31 (m, 7H), 2.26 - 2.17 (m, 3H), 1.77 (d, J = 10.4 Hz, 2H), 1.44 - 1.35 (m, 17H).

Step 2 - 6-chloro-8-isopropyl-2-[2-methyl-4-[(4-piperazin-1-yl-1-piperidyl)sulfonyl]anilino]pyrido[2,3-d]pyrimidin-7-one

A solution of tert-butyl 4-[1-[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonyl-4-piperidyl]piperazine-1-carboxylate (100 mg, 151 umol) in HCl/dioxane (2 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (90 mg, 99% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 560.0 (M+H) ⁺ .

3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JP)

Step 1 - 9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl

A mixture of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.00 g, 3.93 mmol, CAS# 173405-78-2), 4-bromo-3-methyl-1H-benzimidazol-2-one (892 mg, 3.93 mmol, synthesized by steps 1-3 of Intermediate H), Cs ₂ CO ₃ (2.56 g, 7.86 mmol), and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (382 mg, 393 umol) in dioxane (20 mL) was degassed and purged with N ₂ three times. This mixture was then stirred at 100 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 60%-70%, 25 min) to give the title compound (1.17 g, 36% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 9.86 (s, 1H) 7.02 - 6.96 (m, 1H) 6.93 - 6.84 (m, 2H) 3.76 (s, 3H) 3.47 - 3.39 (m, 4H) 2.96 (s, 4H) 1.74 (s, 2H) 1.65 (d, J = 10.0 Hz, 4H) 1.48 (s, 9H) 1.45 - 1.35 (m, 2H). LC-MS(ESI ⁺ )m/z 401.1(M+H) ⁺ .

Step 2 - 9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of tert-butyl 9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.25 mmol) in THF (5 mL) was added t-BuOK (252 mg, 2.25 mmol) and [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (714 mg, 1.87 mmol, intermediate G). The mixture was stirred at −10° C. for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl aq. (2 mL) at 25° C. and diluted with H ₂ O (5 mL) and extracted with EA (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 10 min) to give the title compound (350 mg, 44% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 7.39 - 7.35 (m, 2H) 6.95 - 6.87 (m, 2H) 6.85 - 6.81 (m, 2H) 6.28 (d, J = 7.2Hz, 1H) 5.21 (d, J = 5.2Hz, 1H) 5.02 - 4.92 (m, 2H) 3.80 (s, 3H) 3.77 (s, 3H) 3.46 - 3.40 (m, 4H) 3.04 - 2.98 (m, 1H) 2.95 (s, 4H) 2.87 - 2.77 (m, 1H) 2.61 (d, J = 4.0Hz, 1H) 2.15 (d, J = 2.4 Hz, 1 H) 1.56 - 1.80 (m, 8 H) 1.48 (s, 9 H). LC-MS(ESI ⁺ )m/z 632.4(M+H) ⁺ .

Step 3 - 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 316 umol) in TfOH (0.3 mL) was added TFA (3.08 g, 27.0 mmol). The mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (130 mg, quantitative yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 412.3 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[3-(4-piperidyl)-3,9-diazaspiro[5.5]undecan-9-yl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JQ)

Step 1 - 4-[9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecan-3-yl]piperidine-1-carboxylate tert-butyl

To a solution of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (30.0 mg, 72.9 umol, intermediate JP) in THF (0.5 mL) and DMF (0.5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (217 mg, 1.09 mmol) and KOAc (35.7 mg, 364 umol). After 0.5 h, NaBH(OAc) ₃ (30.9 mg, 145 umol) was added to the mixture, which was then stirred at 25° C. for 12 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18 150×25 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 8 min) to give the title compound (35.0 mg, 79% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 595.7 (M+H) ⁺ .

Step 2 - 3-[3-methyl-2-oxo-4-[3-(4-piperidyl)-3,9-diazaspiro[5.5]undecan-9-yl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecan-3-yl]piperidine-1-carboxylate (35.0 mg, 58.8 umol) in DCM (1 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (29.0 mg, quantitative yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 495.4 (M+H) ⁺ .

tert-Butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (Intermediate JR)

Step 1 - [3-(tert-butoxycarbonylamino)cyclobutyl]4-methylbenzenesulfonate

To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (4.0 g, 21.4 mmol, CAS#389890-43-1), pyridine (10.1 g, 128 mmol), and DMAP (2.61 g, 21.4 mmol) in DCM (80 mL) was added TosCl (7.74 g, 40.6 mmol) at 0° C., then the mixture was stirred at 20° C. for 16 h. Upon completion, the reaction was washed with 20% citric acid (45 ml×3) and brine (50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=10/1 to 1/1) to give the title compound (6.26 g, 85% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.81 - 7.73 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 4.53 - 4.46 (m, 1H), 3.62 - 3.48 (m, 1H), 2.42 (s, 3H), 2.02 - 1.92 (m, 2H), 1.36 (s, 2H), 1.33 (s, 9H), LC-MS(ESI+)m/z 242.0(M-100+H) ⁺ .

Step 2 - 4-[3-(tert-butoxycarbonylamino)cyclobutyl]piperazine-1-carboxylate benzyl

A solution of [3-(tert-butoxycarbonylamino)cyclobutyl] 4-methylbenzenesulfonate (3.0 g, 8.79 mmol), benzyl piperazine-1-carboxylate (4.84 g, 21.8 mmol, CAS#31166-44-6), and DMAP (107 mg, 879 umol) in DMF (40 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100 °C under _N2 atmosphere for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (200 ml), and extracted with EA (50 ml x 4). The organic layers were combined, washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuum to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (970 mg, 25% yield, FA) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.16 (s, 1H), 7.43 - 7.21 (m, 5H), 5.12 - 5.05 (m, 2H), 4.25 - 4.13 (m, 1H), 4.07 - 3.80 (m, 2H), 2.77 - 2.65 (m, 1H), 2.28 - 2.15 (m, 4H), 2.15 - 1.85 (m, 6H), 1.36 (s, 9H), LC-MS(ESI+)m/z 390.2(M+H) ⁺ .

Step 3 - tert-Butyl N-(3-piperazin-1-ylcyclobutyl)carbamate

To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)cyclobutyl]piperazine-1-carboxylate (300 mg, 770 umol, FA) in THF (5 mL) was added Pd/C (100 mg, 10 wt%) under Ar. The suspension was degassed under reduced pressure and purged with H ₂ three times. It was then stirred under an atmosphere of H ₂ (15 psi) below 20° C. for 4 h. Upon completion, the reaction was filtered to obtain the filtrate, which was then concentrated in reduced pressure to provide the title compound (190 mg, 96% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 6.98 (s, 1H), 5.20 - 4.60 (m, 1H), 4.28 - 3.93 (m, 1H), 2.89 (t, J = 4.8 Hz, 2H), 2.42 - 2.17 (m, 5H), 2.00 - 1.95 (m, 2H), 1.44 (s, 9H), 1.32 - 1.21 (m, 3H), 0.89 (s, 1H).

3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JS)

Step 1 - tert-Butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]piperazin-1-yl]cyclobutyl]carbamate

To a solution of 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (228 mg, 548 umol, FA, Intermediate DM) in THF (4 mL) was added TEA (55.5 mg, 548 umol) and the mixture was then stirred at −10° C. for 15 min. Next, tert-butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (140 mg, 548 umol, Intermediate JR) and HOAc (32.9 mg, 548 umol) were added and the mixture was stirred at −10° C. for 15 min. Finally, NaBH(OAc) ₃ (151 mg, 713 umol) was added and the mixture was stirred at −10° C. for 1 h. Upon completion, the reaction was quenched with water (0.3 ml) and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]) to give the title compound (80 mg, 22% yield, FA) as an off-white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.35 (s, 1H), 6.72 - 6.62 (m, 3H), 6.44 - 5.67 (m, 3H), 5.19 (dd, J = 5.2, 12.4 Hz, 1H), 4.83 (s, 1H), 4.05 (s, 1H), 3.54 (d, J = 10.8 Hz, 2H), 3.40 (s, 3H), 3.28 - 3.17 (m, 1H), 2.97 - 2.45 (m, 16H), 2.29 - 2.07 (m, 3H), 1.89 (d, J = 12.4 Hz, 2H), 1.74 (s, 1H), 1.45 (s, 9H), LC-MS(ESI+)m/z 610.2(M+H) ⁺ .

Step 2 - 3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A solution of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]piperazin-1-yl]cyclobutyl]carbamate (60 mg, 91.5 umol, FA) in HCl/dioxane (2.0 mL) was stirred at 20° C. for 1 h. Upon completion, the reaction was concentrated in vacuo to afford the title compound (48 mg, 96% yield, HCl) as an off-white solid. LC-MS (ESI+) m/z 510.4 (M+H) ⁺ .

tert-Butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (Intermediate JT)

Step 1 - [3-(tert-butoxycarbonylamino)cyclobutyl]4-methylbenzenesulfonate

To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (2 g, 10.68 mmol, CAS#98-59-9) in pyridine (15 mL) was added 4-methylbenzenesulfonyl chloride (3.05 g, 16.0 mmol), and the reaction mixture was then stirred at 50° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (30 mL) and extracted with EA (2×20 mL). The combined organic phase was washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=50:1 to PE:EA=3:1, PE:EA=3:1, P1: Rf=0.32) to give the title compound (3.3 g, 90% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.76 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.03 - 4.76 (m, 1H), 3.88 - 3.68 (m, 1H), 2.42 (s, 3H), 2.32 - 2.24 (m, 2H), 2.19 - 2.08 (m, 2H), 1.34 (s, 9H).

Step 2 - 4-[3-(tert-butoxycarbonylamino)cyclobutyl]piperazine-1-carboxylate benzyl

To a solution of [3-(tert-butoxycarbonylamino)cyclobutyl] 4-methylbenzenesulfonate (2.80 g, 8.20 mmol) and benzyl piperazine-1-carboxylate (2.71 g, 12.3 mmol, 2.38 mL) in DMF (15 mL) was added DMAP (50.1 mg, 410 umol). The mixture was stirred at 100° C. for 16 h. Upon completion, the residue was diluted with water (60 mL) and extracted with EA (2×20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (2 g, 62% yield) as a brown oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.35 (s, 5H), 5.13 (s, 2H), 4.82 - 4.67 (m, 1H), 3.97 - 3.79 (m, 1H), 3.55 (s, 4H), 2.58 - 2.31 (m, 6H), 1.80 - 1.78 (m, 2H), 1.43 (s, 9H), LC-MS(ESI+) m/z 390.3(M + H) ⁺ .

Step 3 - tert-Butyl N-(3-piperazin-1-ylcyclobutyl)carbamate

To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)cyclobutyl]piperazine-1-carboxylate (500 mg, 1.28 mmol) in THF (10 mL) was added Pd/C (500 mg, 1.28 mmol, 10 wt%), then the reaction mixture was stirred under H ₂ at 25° C. for 1 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (327 mg, 99% yield) as a white solid with LC-MS (ESI+) m/z 255.8 (M + H) ⁺ .

3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JU)

Step 1 - tert-Butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]piperazin-1-yl]cyclobutyl]carbamate

To a solution of tert-butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (293 mg, 1.15 mmol, Intermediate JT) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (425 mg, 1.15 mmol, Intermediate DM) in DMF (2 mL) and THF (10 mL) was added TEA (116 mg, 1.15 mmol, 159 uL). The mixture was stirred at -10 °C for 10 min, then AcOH (137 mg, 2.29 mmol, 131 uL) was added to the mixture and the mixture was stirred at -10 °C for 20 min. NaBH(OAc) ₃ (316 mg, 1.49 mmol) was then added to the mixture and the mixture was stirred at −10° C. for 1 h. Upon completion, the reaction mixture was quenched with water (0.5 mL) and concentrated in vacuo to give a residue which was purified by reverse phase (0.1% FA condition) to give the title compound (450 mg, 64% yield) as a purple solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.06 (s, 1H), 8.16 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 2.0, 8.4 Hz, 1H), 5.28 (dd, J = 5.2, 13.2 Hz, 1H), 3.67 - 3.60 (m, 1H), 3.57 - 3.54 (m, 2H), 3.29 (s, 3H), 2.95 - 2.83 (m, 1H), 2.74 - 2.65 (m, 1H), 2.64 - 2.52 (m, 4H), 2.43 - 2.20 (m, 9H), 2.18 - 2.16 (m, 2H), 2.02 - 1.93 (m, 1H), 1.78 - 1.75 (m, 2H), 1.70 - 1.56 (m, 3H), 1.36 (s, 9H), 1.30 - 1.15 (m, 2H), LC-MS(ESI ⁺ )m/z 610.4(M+H) ⁺ .

Step 2 - 3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]piperazin-1-yl]cyclobutyl]carbamate (100 mg, 164 umol) in DCM (1 mL) was added HCl/dioxane (3M, 2 mL). The mixture was then stirred at 25° C. for 2 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (89 mg, 99% yield, HCl) as a grey solid. LC-MS (ESI ⁺ ) m/z 510.4 (M + H) ⁺ .

3-[5-[4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate JV)

Step 1- 9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl

To a solution of 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (210 mg, 567 umol, intermediate DM) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (158 mg, 623 umol, CAS# 173405-78-2) in THF (2 mL) and DMF (2 mL) was added HOAc (34.0 mg, 567 umol) and TEA (57.3 mg, 567 umol) at −10° C. and the mixture was stirred for 20 min at −10° C. Then NaBH(OAc) ₃ (180 mg, 850 umol) was added at −10° C. and the reaction mixture was stirred at −10° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (0.5 mL). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 3%-33%, 15 min) to give the title compound (250 mg, 72% yield) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.05 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 2.0, 8.4 Hz, 1H), 5.28 (dd, J = 5.2, 12.8 Hz, 1H), 3.57 (d, J = 12.0 Hz, 2H), 3.27 (s, 4H), 2.95 - 2.83 (m, 1H), 2.73 - 2.58 (m, 4H), 2.55 - 2.51 (m, 3H), 2.38 (d, J = 6.8 Hz, 2H), 2.02 - 1.95 (m, 1H), 1.78 (d, J = 12.8 Hz, 2H), 1.69 (dd, J = 3.6, 7.2 Hz, 1H), 1.54 - 1.47 (m, 4H), 1.40 - 1.32 (m, 15H), 1.32 - 1.19 (m, 4H).

Step 2 - 3-[5-[4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 164 umol) in DCM (0.2 mL) was added HCl/dioxane (4 M, 1.00 mL) and the reaction mixture was then stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (89 mg, 99% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 509.4 (M+H) ⁺ .

7-Bromoheptanal (Intermediate JW)

To a solution of 7-bromoheptan-1-ol (100 mg, 512 umol, CAS#10160-24-4) in DCM (3 mL) was added DMP (260 mg, 615 umol). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was quenched with Na ₂ S ₂ O ₃ .5H ₂ O (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound (95 mg, 95% yield) as a white solid.

3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (Intermediate JX)

Step 1 - 2-(methylamino)-3-nitro-benzoic acid

To a solution of MeNH ₂ /EtOH (54.0 mmol, 200 mL, 30% solution) was added 2-fluoro-3-nitro-benzoic acid (10.0 g, 54.0 mmol) portionwise at 0° C. The reaction mixture was then stirred at 20° C. for 2 h. Upon completion, the mixture was concentrated in vacuo. The residue was diluted with water (100 mL), acidified with citric acid to pH=3-5, stirred, and filtered. The filter cake was dried in vacuo to give the title compound (9.60 g, 91% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 13.41 (s, 1H), 8.62 (s, 1H), 8.04 (dd, J = 1.6, 8.0 Hz, 1H), 7.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 2.70 (s, 3H).

Step 2 - 3-Methyl-4-nitro-1H-benzimidazol-2-one

To a solution of 2-(methylamino)-3-nitro-benzoic acid (8.60 g, 43.8 mmol) and DIPEA (17.0 g, 132 mmol) in t-BuOH (200 mL) was added DPPA (12.1 g, 43.8 mmol) dropwise at 0° C. The reaction mixture was then stirred at 85° C. for 12 h. Upon completion, the mixture was diluted with MeOH (100 mL), cooled to 10-20° C., filtered, and the filter cake was dried in vacuum to give the title compound (6.80 g, 80% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.61 (s, 1H), 7.58 (dd, J = 0.8, 8.0 Hz, 1H), 7.30 (dd, J = 0.8, 8.0 Hz, 1H), 7.18 - 7.07 (m, 1H), 3.34 (s, 3H).

Step 3 - 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of 3-methyl-4-nitro-1H-benzimidazol-2-one (7.20 g, 37.3 mmol) in THF (70 mL) was added t-BuOK (8.37 g, 74.6 mmol) at −10 to 0° C. After 1 h, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (21.3 g, 55.9 mmol, intermediate H) in THF (50 mL) was added to the above mixture and the reaction mixture was stirred at 0 to 20° C. for 12 h. Upon completion, the mixture was acidified with FA to pH=3-5, diluted with water (300 mL) and extracted with EA (2×300 mL). The organic layer was washed with brine (200 mL) and then concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (5.80 g, 37% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.69 (dd, J = 0.8, 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.27 - 7.17 (m, 3H), 6.93 - 6.78 (m, 2H), 5.67 (dd, J = 5.2, 12.8 Hz, 1H), 4.94 - 4.62 (m, 2H), 3.72 (s, 3H), 3.41 (s, 3H), 3.11 - 2.98 (m, 1H), 2.89 - 2.70 (m, 2H), 2.17 - 2.08 (m, 1H).

Step 4 - 3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.00 g, 4.71 mmol) in TFA (20 mL) was added TfOH (2 mL). The reaction mixture was stirred at 60° C. for 12 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (900 mg, 63% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.19 (s, 1H), 7.68 (dd, J = 0.8, 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 5.51 (dd, J = 5.2, 12.8 Hz, 1H), 3.41 (s, 3H), 2.95 - 2.85 (m, 1H), 2.80 - 2.60 (m, 2H), 2.13 - 2.06 (m, 1H).

Step 5 - 3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of 3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (850 mg, 2.79 mmol) in THF (50 mL) was added Pd/C (200 mg, 10% wt). The reaction mixture was stirred at 20° C. under an atmosphere of H ₂ (15 Psi) for 12 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.70 g, 91% yield) as a pink solid. LC-MS (ESI ⁺ ) m/z 275.1 (M+H) ⁺ .

3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (Intermediate JY)

To a solution of 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (310 mg, 730 umol, intermediate JX) in a mixture of EtOH (5 mL) and H ₂ O (5 mL) was added Fe (203 mg, 3.65 mmol) and NH ₄ Cl (390 mg, 7.30 mmol). The mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was then partitioned between EA (10 ml) and water (10 ml). The organic layer was collected and the aqueous layer was extracted with EA (2×8 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (285 mg, 98% yield) as a yellow solid. LCMS (ESI ^<+> ) m/z 394.9 (M+H) ^<+> .

3-[4-(7-bromoheptylamino)-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (Intermediate JZ)

To a solution of 3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (50.0 mg, 126 umol, intermediate JY) in a mixed solvent of THF (2 mL) and DMF (0.5 mL) was added 7-bromoheptanal (25.7 mg, 133 umol, intermediate JW) and tetraisopropoxytitanium (72.0 mg, 253 umol) at 25° C. for 16 h. Then, NaBH ₃ CN (15.9 mg, 253 umol) was added to the mixture and the reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was partitioned between H ₂ O (20 mL) and EA (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by prep-TLC (SiO ₂ , PE:EA=1:1) to give the title compound (25 mg, 34% yield) as a white solid. LCMS (ESI ⁺ ) m/z 573.1 (M+H) ⁺ .

6-Chloro-8-isopropyl-2-(4-piperidylamino)pyrido[2,3-d]pyrimidin-7-one (Intermediate KA)

Step 1 - 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]piperidine-1-carboxylate tert-butyl

To a solution of 6-chloro-8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (450 mg, 1.49 mmol, intermediate KP) in DMSO (1 mL) was added DIEA (192 mg, 1.49 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (358 mg, 1.79 mmol, CAS#502482-34-0). The mixture was stirred at 90° C. for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 65%-75%, 22 min) to give the title compound (800 mg, 63% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.62 - 8.56 (m, 1H), 8.05 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 6.4 Hz, 1H), 5.86 - 5.61 (m, 1H), 4.09 - 3.98 (m, 1H), 3.92 (d, J = 12.4 Hz, 2H), 2.97 - 2.82 (m, 2H), 1.90 - 1.80 (m, 2H), 1.54 - 1.48 (m, 6H), 1.40 (s, 12H). LCMS(ESI ⁺ ) m/z 422.0(M+H) ⁺ .

Step 2 - 6-chloro-8-isopropyl-2-(4-piperidylamino)pyrido[2,3-d]pyrimidin-7-one

To a solution of tert-butyl 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]piperidine-1-carboxylate (170 mg, 402 umol) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound (175 mg, 99% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 321.9 (M+H) ⁺ .

6-Chloro-8-isopropyl-2-[[1-(1H-pyrazol-4-ylsulfonyl)-4-piperidyl]amino]pyrido[2,3-d]pyrimidin-7-one (Intermediate KB)

To a solution of 6-chloro-8-isopropyl-2-(4-piperidylamino)pyrido[2,3-d]pyrimidin-7-one (175 mg, 401 umol, TFA, intermediate KA) in DMF (4 mL) was added DIEA (155 mg, 1.20 mmol) and 1H-pyrazole-4-sulfonyl chloride (93.6 mg, 562 umol, CAS# 438630-64-9). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 9 min) to give the title compound (100 mg, 55% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 13.76 (s, 1H), 8.57 (s, 1H), 8.40 - 8.10 (m, 1H), 8.04 (s, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 5.86 - 5.51 (m, 1H), 3.81 (d, J = 15.2 Hz, 1H), 3.47 (d, J = 12.0 Hz, 2H), 2.49 - 2.46 (m, 1H), 2.45 - 2.35 (m, 1H), 2.03 - 1.89 (m, 2H), 1.70 - 1.57 (m, 2H), 1.48 (d, J = 6.8 Hz, 6H). LCMS (ESI ⁺ ) m/z 452.0 (M+H) ⁺ .

6-(Difluoromethyl)-2-methylsulfonyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (Intermediate KC)

Step 1 - 5-Bromo-2-methylsulfanyl-N-spiro[2.4]heptan-7-yl-pyrimidin-4-amine

To a solution of 5-bromo-2-chloro-N-spiro[2.4]heptan-7-yl-pyrimidin-4-amine (6.70 g, 22.1 mmol, synthesized by step 1 of intermediate HX) in DMF (70 mL) was added NaSMe (2.54 g, 36.2 mmol, 2.31 mL) at 0° C. The reaction was stirred at 25° C. for 16 h. Upon completion, the reaction was diluted with EA (150 mL). The organic layer was washed with water (2×100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give the title compound (6.2 g, 89% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 315.8 (M+1) ⁺ .

Step 2 - (E)-3-[2-methylsulfanyl-4-(spiro[2.4]heptan-7-ylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester

To a solution of 5-bromo-2-methylsulfanyl-N-spiro[2.4]heptan-7-yl-pyrimidin-4-amine (6.20 g, 19.7 mmol), TEA (2.00 g, 19.7 mmol, 2.75 mL), and Pd( _PPh3 ) ₄ (2.28 g, 1.97 mmol) in DMF (100 mL) was added methyl prop-2-enoate (13.0 g, 151 mmol, 13.6 mL, CAS#96-33-3). The reaction was then stirred at 90 °C under _N2 for 32 h. Upon completion, the reaction was diluted with EA (200 mL). The organic layer was washed with water (2 x 100 mL), dried over _{anhydrous Na2SO4} , and filtered. The filtrate was concentrated in vacuo, then the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/4) to give the title compound (3.9 g, 61% yield) as a yellow solid: LC-MS (ESI ⁺ ) m/z 320.3 (M+1) ⁺ .

Step 3 - 2-Methylsulfanyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one

To a solution of methyl (E)-3-[2-methylsulfanyl-4-(spiro[2.4]heptan-7-ylamino)pyrimidin-5-yl]prop-2-enoate (2.80 g, 8.77 mmol) in NMP (30 mL) was added DBU (6.67 g, 43.8 mmol, 6.61 mL). The reaction was stirred at 150° C. under N ₂ for 2 h. Upon completion, the reaction was diluted with EA (300 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuum and then the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1) to give the title compound (2.3 g, 91% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 288.0 (M+1) ⁺ .

Step 4 - 6-[chloro(difluoro)methyl]-2-methylsulfanyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one

To a 15 mL vial equipped with a stir bar was added 4-phenylpyridine N-oxide (2.38 g, 13.9 mmol), 2-methylsulfanyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 6.96 mmol), Ru(bpy) _3Cl2.6H2O (52.1 mg, 69.5 umol) in dry ACN (2 mL). Then ₂ -chloro-2,2-difluoro- _acetic acid (2-chloro-2,2-difluoro-acetyl) (4.23 g, 17.40 mmol, CAS# 2834-23-3) was added. The vial was sealed and placed under nitrogen and added. The reaction was stirred and irradiated with a 34 W blue LED lamp (2 cm away) for 16 hours, using cooling water to maintain the reaction temperature at 25°C. Upon completion, the reaction was concentrated in vacuo. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to afford the title compound (2.59 g, 100% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 372.0 (M+1) ⁺ .

Step 5 - N-[5-isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]acetamide

A mixture of 6-[chloro(difluoro)methyl]-2-methylsulfanyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.69 mmol), Pd/C (318 mg, 268 umol, 10 wt%), Na ₂ CO ₃ (427 mg, 4.03 mmol) in THF (20 mL) was degassed and purged with H ₂ three times. This mixture was then stirred under H ₂ (30 Psi) at 25° C. under H ₂ atmosphere for 1 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was then purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 60%-70%, 20 min) to give the title compound (107 mg, 11% yield). LC-MS (ESI ⁺ ) m/z 338.0 (M+1) ⁺ .

Step 6 - 6-(difluoromethyl)-2-methylsulfonyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-(difluoromethyl)-2-methylsulfanyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 296 umol) in DCM (2 mL) was added m-CPBA (240 mg, 1.19 mmol, 85% solution). The mixture was stirred at 40° C. for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (5 mL) at 25° C. and then extracted with EA (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-TLC (SiO ₂ , PE:EA=1:1) to give the title compound (50 mg, 40% yield). ^1H NMR (400 MHz, _CDCl3 ) δ 9.04 (s, 1H), 8.07 (s, 1H), 7.02 - 6.69 (m, 1H), 6.01 - 5.69 (m, 1H), 3.40 (s, 3H), 2.59 - 2.49 (m, 1H), 2.25 - 2.13 (m, 2H), 1.97 - 1.85 (m, 1H), 1.56 (s, 1H), 1.47 - 1.42 (m, 1H), 0.75 - 0.59 (m, 3H), 0.03 - 0.01 (m, 1H). LC-MS(ESI ⁺ )m/z 370.0(M+1) ⁺ .

4-[[6-(difluoromethyl)-7-oxo-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate KD)

Step 1 - 2-(4-benzylsulfanyl-2-methyl-anilino)-6-(difluoromethyl)-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one

A mixture of 6-(difluoromethyl)-2-methylsulfonyl-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (45.0 mg, 121 umol, Intermediate KC), 4-benzylsulfanyl-2-methyl-aniline (83.8 mg, 365 umol, Intermediate DE), and TFA (138 mg, 1.22 mmol, 90.2 uL) in IPA (2 mL) was stirred at 90° C. for 32 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was then purified by prep-TLC (SiO ₂ , PE:EA=1:1) to give the title compound (35 mg, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 519.4 (M+1) ⁺ .

Step 2 - 4-[[6-(difluoromethyl)-7-oxo-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-anilino)-6-(difluoromethyl)-8-spiro[2.4]heptan-7-yl-pyrido[2,3-d]pyrimidin-7-one (26.9 mg, 51.9 umol) in H ₂ O (0.06 mL), ACN (1 mL) and AcOH (0.1 mL) was added NCS (17.3 mg, 129 umol). The mixture was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25 °C and then extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was then purified by prep-TLC (SiO ₂ , PE/EA=1/1) to give the title compound (20 mg, 77% yield) as a white solid: LC-MS (ESI ⁺ ) m/z 495.1 (M+1) ⁺ .

4-Bromo-5-methoxy-3-methyl-1H-benzimidazol-2-one (Intermediate KE)

Step 1 - 2-Bromo-3-fluoro-1-methoxy-4-nitro-benzene

To a mixture of 2-bromo-1,3-difluoro-4-nitro-benzene (5.00 g, 21.01 mmol, from CAS# 103977-78-2) in MeOH (50 mL) was added NaOMe (1.14 g, 21.0 mmol) at 0 °C. The mixture was warmed to 20 °C and stirred for 2 h. Upon completion, the mixture was poured into water (60 mL) and the aqueous phase was extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with brine (2 x 40 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give the crude product. The crude product was triturated with PE:EA = 20:1 (10 mL) to give the title compound (1.80 g, 34% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 8.14 (dd, J = 8.4, 9.2 Hz, 1H), 6.81 (dd, J = 1.6, 9.2 Hz, 1H), 4.04 (s, 3H).

Step 2 - 2-Bromo-3-methoxy-N-methyl-6-nitro-aniline

To a mixture of 2-bromo-3-fluoro-1-methoxy-4-nitro-benzene (1.60 g, 6.40 mmol) in THF (20 mL) was added MeNH ₂ (2M, 4.80 mL) and the mixture was stirred at 20° C. for 2 h. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50:1 to 10:1) to give the title compound (1.40 g, 83% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, J = 9.6 Hz, 1H), 6.73 (s, 1H), 6.44 (d, J = 9.2 Hz, 1H), 3.97 (s, 3H), 3.09 (d, J = 5.2 Hz, 3H).

Step 3 - 3-Bromo-4-methoxy-N2-methyl-benzene-1,2-diamine

To a mixture of 2-bromo-3-methoxy-N-methyl-6-nitro-aniline (1.40 g, 5.36 mmol) in THF (10 mL) and MeOH (10 mL) was added platinum (104 mg, 53.6 umol, 10 wt%) under H ₂ (15 psi) and stirred for 2 h at 20° C. Upon completion, the mixture was filtered and concentrated to give the title compound (1.20 g, 96% yield) as a yellow solid.

Step 4 - 4-Bromo-5-methoxy-3-methyl-1H-benzimidazol-2-one

To a mixture of 3-bromo-4-methoxy-N2-methyl-benzene-1,2-diamine (1.1 g, 4.76 mmol) in CH ₃ CN (20 mL) was added CDI (1.16 g, 7.14 mmol) and the mixture was stirred at 90° C. for 3 h. Upon completion, the mixture was concentrated to remove CH ₃ CN and then H ₂ O (10 mL) was added to the mixture. The mixture was filtered to obtain a filter cake which was dried to give the title compound (1.00 g, 81% yield) as a brown solid. ^1H NMR (400 MHz, _CDCl3 ) δ 6.89 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 2.72 (d, J = 2.4 Hz, 1H).

Step 5 - 4-Bromo-5-methoxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of 7-bromo-6-methoxy-1-methyl-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 3.90 mmol) in THF (30 mL) was added NaH (234 mg, 5.85 mmol, 60% dispersion in mineral oil) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Then, SEM-Cl (0.98 g, 5.85 mmol) was added to the above solution and the mixture was stirred at 65° C. for 10 h. Upon completion, the mixture was quenched with H ₂ O (30 mL) and extracted with EA (2×30 mL). The organic layer was washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in reduced pressure. The mixture was purified by a silica gel column (PE:EA=20:1) to give the title compound (1.30 g, 86% yield) as a yellow oil: LC-MS (ESI ⁺ ) m/z 387.0 (M+H) ⁺ .

3-(5-Methoxy-3-methyl-4-(4-(methylamino)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate KF)

Step 1 - N-[1-[5-methoxy-3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-4-piperidyl]-N-methyl-tert-butyl carbamate

A solution of 4-bromo-5-methoxy-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (250 mg, 645 umol, intermediate KE), tert-butyl N-methyl-N-(4-piperidyl)carbamate (276 mg, 1.29 mmol, CAS #108612-54-0), (t-Bu)PhCPhos Pd G4 (35 mg, 64.5 umol) and t-BuOK (217 mg, 1.94 mmol) in dioxane (8 mL) was stirred at 85 °C under N for ₁₆ h. Upon completion, the reaction mixture was diluted with EtOAC (40 mL) and washed with brine ( _{2 x 20 mL). The organic layer was separated and dried over Na2SO4 and} concentrated in vacuo. The residue was purified by reverse phase (FA conditions) to give the title compound (35.0 mg, 10% yield). ^1H NMR (400 MHz, MeOD) δ 7.04 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.31 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.67 - 3.53 (m, 4H), 3.39 (s, 1H), 3.06 - 2.99 (m, 2H), 2.87 (s, 3H), 2.09 - 1.92 (m, 2H), 1.68 (d, J = 12 Hz, 2H), 1.53 (s, 9H), 1.39 - 1.31 (m, 2H), 0.98 - 0.89 (m, 2H), 0.00 (s, 9H).

Step 2 - (1-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)(methyl)carbamate tert-butyl

To a solution of tert-butyl N-[1-[5-methoxy-3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (40.0 mg, 76.8 umol) in THF (5 mL) was added TBAF (200 mg, 768 umol) at 25° C. The reaction was warmed to 70° C. and stirred for 16 h. Upon completion, the reaction mixture was diluted with EtOAc (60 mL) and washed with brine (4×30 mL). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (29.0 mg, 96% yield) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 6.78 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.61 (s, 3H), 3.38 - 3.20 (m, 2H), 3.01 - 2.90 (m, 2H), 2.79 (s, 3H), 1.97 - 1.82 (m, 2H), 1.64 - 1.51 (m, 2H), 1.48 (s, 9H).

Step 3 - (1-(5-methoxy-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)(methyl)carbamate tert-butyl

To a solution of tert-butyl N-[1-(5-methoxy-3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidyl]-N-methyl-carbamate (24.0 mg, 61.4 umol) in THF (3 mL) was added tBuOK (13.8 mg, 122 umol) at 0° C. and the mixture was stirred for 30 min at 0° C. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (37.5 mg, 98.3 umol, intermediate G) in THF (0.5 mL) was added slowly to the mixture and the reaction was stirred for 2 h at 0° C. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl solution (1 mL) and diluted with water (10 mL). The mixture was then extracted with EtOAc (2×40 mL). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by prep-TLC (DCM:EtOAc=3:1, Rf=0.5) to give the title compound (36 mg, 94% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 622.2 (M+H) ⁺ .

Step 4 - 3-(5-methoxy-3-methyl-4-(4-(methylamino)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl N-[1-[5-methoxy-1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (30.0 mg, 48.2 umol) in TFA (0.4 mL) was added TfOH (0.08 mL) at 25° C. The reaction mixture was warmed to 70° C. and stirred for 3 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 3%-33%, 11 min) to give the title compound (11.0 mg, 56% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 402.1 (M+H) ⁺ .

3-[5-Methoxy-3-methyl-4-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate KG)

Step 1 - 4-[[[1-[1-(2,6-dioxo-3-piperidyl)-5-methoxy-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate tert-butyl

To a solution of 3-[5-methoxy-3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (110 mg, 213 umol, TFA, intermediate KF) in THF (1 mL) was added TEA (59.4 uL, 426 umol). 4-formylpiperidine-1-carboxylate tert-butyl (40.9 mg, 192 umol, CAS# 137076-22-3) and HOAc (12.2 uL, 213 umol) were then added and the mixture was stirred at -10°C for 0.5 hours. NaBH(OAc) ₃ (67.8 mg, 320 umol) was then added and the mixture was stirred at -10°C for 1.5 hours. Upon completion, the mixture was quenched with water (1 mL), filtered, and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to give the title compound (80.0 mg, 62% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.06 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.32 - 5.27 (m, 1H), 3.96 - 3.93 (m, 2H), 3.77 (s, 3H), 3.60 (s, 3H), 3.38 - 3.33 (m, 2H), 2.99 - 2.97 (m, 2H), 2.93 - 2.81 (m, 2H), 2.78 - 2.57 (m, 7H), 2.53 - 2.51 (m, 2H), 2.01 - 1.66 (m, 8H), 1.40 (s, 9H), 1.11 - 0.95 (m, 2H). LC-MS(ESI ⁺ )m/z 599.2(M+H) ⁺ .

Step 2 - 3-[5-Methoxy-3-methyl-4-[4-[methyl(4-piperidylmethyl)amino]-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A solution of tert-butyl 4-[[[1-[1-(2,6-dioxo-3-piperidyl)-5-methoxy-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]piperidine-1-carboxylate (50.0 mg, 83.4 umol) in HCl/dioxane (1 mL) was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (40.0 mg, 89% yield, HCl) as a yellow solid. LC-MS (ESI ⁺ ) m/z 499.1 (M+H) ⁺ .

3-[5-[4-[[4-(3-aminopropyl)piperazin-1-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate KH)

Step 1 - N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]piperazin-1-yl]propyl]carbamic acid tert-butyl

To a solution of tert-butyl N-(3-piperazin-1-ylpropyl)carbamate (50.0 mg, 205 umol, CAS#874831-60-4) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (85.5 mg, 205 umol, FA, intermediate DM) in a mixture of THF (1 mL) and DMF (1 mL) was added KOAc (201 mg, 2.05 mmol). The mixture was stirred at 0° C. for 5 min. Then NaBH(OAc) ₃ (87.0 mg, 410 umol) was added and the mixture was stirred at 0° C. for 30 min. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) and then concentrated in vacuo to give a residue which was purified by pre-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 0%-23%, 9 min) to give the title compound (88 mg, 71% yield) as a colorless oily liquid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.05 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.85 - 6.76 (m, 2H), 6.62 (dd, J = 1.6, 8.4 Hz, 1H), 5.28 (dd, J = 5.2, 12.8 Hz, 2H), 3.57 (d, J = 11.6 Hz, 8H), 2.96 - 2.88 (m, 6H), 2.74 - 2.70 (m, 2H), 2.42 (s, 3H), 2.33 (t, J = 7.2 Hz, 3H), 2.19 (d, J = 7.2 Hz, 2H), 2.01 - 1.94 (m, 1H), 1.78 (d, J = 11.2 Hz, 2H), 1.57 - 1.50 (m, 2H), 1.37 (s, 9H), 1.29 - 1.18 (m, 2H). LC-MS(ESI ⁺ )m/z 598.2(M+H) ⁺ .

Step 2 - 3-[5-[4-[[4-(3-aminopropyl)piperazin-1-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]piperazin-1-yl]propyl]carbamate (60.0 mg, 100 umol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to afford the title compound (45.0 mg, 90% yield) as a colorless oily liquid. LC-MS (ESI ⁺ ) m/z 498.1 (M+H) ⁺ .

Tributyl-(3-isopropyl-2-methyl-imidazol-4-yl)stannane (Intermediate KI)

Step 1 - 5-bromo-1-isopropyl-2-methyl-imidazole and 4-bromo-1-isopropyl-2-methyl-imidazole

To a mixture of 1-isopropyl-2-methyl-imidazole (10.0 g, 80.5 mmol, CAS#87606-45-1) in ACN (100 mL) was added NBS (14.3 g, 80.5 mmol) at 0° C., then the reaction mixture was stirred for 16 h at 25° C. Upon completion, the residue was diluted with water (80 mL) and extracted with EA (3×100 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give 5-bromo-1-isopropyl-2-methyl-imidazole (8.00 g, 49% yield, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.79 (s, 1H), 4.57 (d, J = 7.0, 14.0 Hz, 1H), 2.37 (s, 3H), 1.46 (d, J = 7.2 Hz, 6H) as a white oil, and 4-bromo-1-isopropyl-2-methyl-imidazole (2.00 g, 12% yield, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.29 (s, 1H), 4.34 (td, J = 6.4, 13.2 Hz, 1H), 2.27 (s, 3H), 1.32 (d, J = 6.4 Hz, 6H) were obtained as a white oil.

Step 2 - Tributyl-(3-isopropyl-2-methyl-imidazol-4-yl)stannane

To a mixture of 5-bromo-1-isopropyl-2-methyl-imidazole (1.50 g, 7.39 mmol) in dioxane (30 mL) was added Pd ₂ (dba) ₃ (676 mg, 738 umol) and LiCl (939 mg, 22.1 mmol) and tricyclohexylphosphane (2.07 g, 7.39 mmol) and tributyl(tributylstannyl)stannane (42.8 g, 73.8 mmol), then the reaction mixture was stirred at 100° C. for 12 h. Upon completion, the reaction mixture was quenched with CsF(aq) (50 mL) and concentrated in vacuo to give the title compound (3 g, 98% yield) as a brown oil. LC-MS (ESI ⁺ ) m/z 412.6 (M+H) ⁺ .

4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate KJ)

Step 1 - N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-amine

To a mixture of tributyl-(3-isopropyl-2-methyl-imidazol-4-yl)stannane (3.00 g, 7.26 mmol, intermediate KI) and N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (2.98 g, 7.26 mmol, intermediate EA) in dioxane (2 mL) was added K ₂ CO ₃ (3.01 g, 21.7 mmol), CuI (138 mg, 725 umol) and Pd(PPh ₃ ) ₂ Cl ₂ (509 mg, 725 umol). The reaction mixture was then stirred at 110° C. for 12 h. Upon completion, the residue was diluted with water (30 mL) and extracted with EA (3×60 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=50:1 to PE:EA=1:1). The residue was then purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 27% to 57%, 10 min) to give the title compound (2 g, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 498.4 (M+H) ⁺ .

Step 2 - 4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a mixture of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (65.0 mg, 130 umol) in ACN (1 mL), HOAc (0.3 mL), and H ₂ O (0.1 mL) was added NCS (52.3 mg, 391 umol). The reaction mixture was then stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (60 mg, 86.0% yield, HOAC) as a yellow oil. LC-MS (ESI ⁺ ) m/z 474.2 (M+H) ⁺ .

3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate KL)

Step 1 - 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl

To a solution of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (9.00 g, 26.6 mmol, intermediate H), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (12.3 g, 39.9 mmol, CAS# 286961-14-6) and XPhos-Pd-G2 (2.09 g, 2.66 mmol) in dioxane (150 mL) and H ₂ O (15 mL) was added K ₃ PO ₄ (11.3 g, 53.2 mmol). The reaction mixture was stirred at 80 °C under N ₂ for 4 h. Upon completion, the reaction mixture was filtered. The filtrate was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuum. The residue was triturated with sat. NH ₄ Cl (2×50 mL), water (2×50 mL) and EA (2×50 mL) and filtered. The solid was dried in vacuum to give the title compound (8.00 g, 68% yield) as an off-white solid. LC-MS (ESI ⁺ ) m/z 441.1 (M+H) ⁺ .

Step 2 - 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8.00 g, 18.2 mmol) in DMF (20 mL) and THF (60 mL) was added H ₂ , Pd/C (1.00 g, 10 wt%) and Pd(OH) ₂ (1.00 g, 3.56 mmol, 50 wt%). The mixture was degassed and purged with nitrogen three times, then degassed and purged with hydrogen three times. The mixture was stirred at 25° C. under an atmosphere of hydrogen (15 psi) for 16 h. Upon completion, the reaction mixture was filtered and the combined filtrate was concentrated in vacuo to give the title compound (5.60 g, 70% yield) as a white solid. ^1H NMR (400MHz, DMSO- _d6 ) δ 11.10 (s, 1H), 7.06 - 6.92 (m, 3H), 5.38 (m, 1H), 4.18 - 3.96 (m, 2H), 3.60 (s, 3H), 3.48 - 3.39 (m, 1H), 2.97 - 2.81 (m, 3H), 2.76 - 2.61 (m, 2H), 2.05 - 1.94 (m, 1H), 1.81 (m, 2H), 1.65 - 1.50 (m, 2H), 1.47 - 1.40 (m, 9H). LC-MS(ESI ⁺ )m/z 287.4 (387.3) ⁺ .

Step 3 - 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate (100 mg, 226 umol) in DCM (1 mL) was added HCl/dioxane (1 mL). The reaction mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (85.0 mg, 99% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 343.3 (M+H) ⁺ .

6-Chloro-8-cyclopentyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate KM)

Step 1 - 8-Cyclopentyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 7.65 mmol, intermediate HN) in DCM (20 mL) was added m-CPBA (6.21 g, 30.6 mmol, 85% solution). The mixture was stirred at 40° C. for 3 h. Upon completion, the reaction mixture was quenched with Na ₂ CO ₃ aq. (10 mL) at 25° C. and then extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (2.00 g, 89% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 293.9 (M+1) ⁺ .

Step 2 - 6-Chloro-8-cyclopentyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 340.9 umol) in DMF (1 mL) was added NCS (500 mg, 3.75 mmol). The mixture was stirred at 70° C. for 16 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The crude product was then purified by reverse phase HPLC (0.1% FA condition) to give the title compound (280 mg, 24% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 327.9(M+1) ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.94 (s, 1H), 7.96 (s, 1H), 6.08 - 5.92 (m, 1H), 3.40 (s, 3H), 2.32 - 2.23 (m, 2H), 2.22 - 2.13 (m, 2H), 2.04 - 1.96 (m, 2H), 1.77 - 1.70 (m, 2H).

6-Chloro-8-cyclopentyl-2-[2-methyl-4-(2-oxopiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one (Intermediate KN)

Step 1 - 4-(4-amino-3-methyl-phenyl)-3-oxo-piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.00 g, 9.99 mmol, CAS#76003-29-7) and 4-iodo-2-methyl-aniline (2.79 g, 11.9 mmol, CAS#13194-68-8) in dioxane (35 mL) was added CuI (1.90 g, 9.99 mmol), K ₃ PO ₄ (5.30 g, 24.9 mmol) and N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (2.84 g, 19.9 mmol). The mixture was then purged with N ₂ three times and stirred at 110 °C for 10 h. Upon completion, the mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=10:1 to 1:5) to give the title compound (2.50 g, 81% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.83 (d, J=2.0 Hz, 1H), 6.79 (d, J=2.4, 8.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.88 (s, 2H), 4.03 - 3.96 (m, 2H), 3.66 - 3.54 (m, 4H), 2.03 (s, 3H), 1.44 (s, 9H). LC-MS(ESI ⁺ )m/z 306.0(M+H) ⁺ .

Step 2 - 4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]-3-oxo-piperazine-1-carboxylate tert-butyl

To a solution of tert-butyl 4-(4-amino-3-methyl-phenyl)-3-oxo-piperazine-1-carboxylate (400 mg, 1.31 mmol) and 6-chloro-8-cyclopentyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin- ₇ -one (429 mg, 1.31 mmol, intermediate KM) in dioxane (10 mL) was added _Cs2CO3 (853 mg, 2.62 mmol) and Pd-PEPPSI-IHeptCl 3-chloropyridine (127 mg, 130 umol). The mixture was then purged with _N2 three times and stirred at 80 °C for 12 h. Upon completion, the mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 55%-85%, 10 min) to give the title compound (85.0 mg, 11% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 553.3 (M+H) ⁺ .

Step 3 - 6-chloro-8-cyclopentyl-2-[2-methyl-4-(2-oxopiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one

To a solution of tert-butyl 4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]-3-oxo-piperazine-1-carboxylate (80.0 mg, 144 umol) was added HCl/dioxane (2 mL) and the mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (70.0 mg, 98% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 452.9 (M+H) ⁺ .

4-[4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]-3-oxo-piperazin-1-yl]cyclohexanecarbaldehyde (Intermediate KO)

Step 1 - 6-chloro-8-cyclopentyl-2-[4-[4-[4-(hydroxymethyl)cyclohexyl]-2-oxo-piperazin-1-yl]-2-methyl-anilino]pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-chloro-8-cyclopentyl-2-[2-methyl-4-(2-oxopiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one (70.0 mg, 154 umol, HCl, intermediate KN) in DMF (0.5 mL) and THF (1 mL) was added TEA (718.45 umol, 0.1 mL). Then 4-(hydroxymethyl)cyclohexanone (29.7 mg, 231 umol, CAS#38580-68-6) and AcOH (1.75 mmol, 0.1 mL) were added and the mixture was stirred at 25° C. for 0.2 h. Then NaBH(OAc) ₃ (65.5 mg, 309 umol) was added and the mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was filtered to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 15 min) to give the title compound (55.0 mg, yield 62%) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.49 (s, 1H), 8.70 (s, 1H), 8.20 - 8.10 (m, 1H), 7.41 - 7.33 (m, 1H), 7.29 - 7.10 (m, 2H), 5.81 - 5.62 (m, 1H), 4.33 (s, 1H), 3.66 - 3.56 (m, 2H), 3.28 (s, 2H), 3.22 (s, 2H), 2.89 - 2.80 (m, 2H), 2.20 (s, 3H), 2.17 - 2.06 (m, 2H), 1.91 - 1.77 (m, 2H), 1.72 - 1.15 (m, 12H), 0.97 - 0.84 (m, 1H), LC-MS(ESI ⁺ )m/z 565.2(M+H) ⁺ .

Step 2 - 4-[4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]-3-oxo-piperazin-1-yl]cyclohexanecarbaldehyde

To a solution of 6-chloro-8-cyclopentyl-2-[4-[4-[4-(hydroxymethyl)cyclohexyl]-2-oxo-piperazin-1-yl]-2-methyl-anilino]pyrido[2,3-d]pyrimidin-7-one (50.0 mg, 88.4 umol) in DCM (1.5 mL) was added DMP (56.2 mg, 132 umol) at 0° C., and the mixture was then stirred at 25° C. for 1 h. Upon completion, the mixture was diluted with DCM (2 mL), then quenched with saturated Na ₂ S ₂ O ₃ (3 mL) and saturated NaHCO ₃ (3 mL), and stirred at 25° C. for 10 min. Thereafter, the mixture was extracted with DCM (3 mL×3). The combined organic layers were then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (47.0 mg, 94% yield) as a yellow solid: LC-MS (ESI ⁺ ) m/z 563.3 (M+H) ⁺ .

6-Chloro-8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate KP)

Step 1 - 8-Isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.20 g, 9.35 mmol, intermediate DN) in DCM (20.0 mL) was added m-CPBA (7.59 g, 37.0 mmol, 85% solution). The mixture was stirred at 40 °C for 3 h. Upon completion, the reaction mixture was quenched with Na ₂ CO ₃ aq. (100 mL) at 25 °C and then extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (2.10 g, 84% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.27 (s, 1H), 8.07 (d, J = 9.6 Hz, 1H), 6.87 (d, J = 9.6 Hz, 1H), 5.65 (td, J = 6.8, 13.6 Hz, 1H), 3.46 (s, 3H), 1.56 (d, J = 7.2 Hz, 6H). LC-MS(ESI ⁺ )m/z 267.9(M+H) ⁺ .

Step 2 - 6-Chloro-8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 374 umol) in DMF (1.50 mL) was added NCS (149 mg, 1.12 mmol). The mixture was stirred at 70° C. for 16 h. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (74.0 mg, 65% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 - 9.25 (m, 1H), 8.68 - 8.37 (m, 1H), 5.90 - 5.58 (m, 1H), 3.48 (d, J = 2.4 Hz, 3H), 1.58 (s, 6H). LC-MS(ESI ⁺ )m/z 301.8(M+H) ⁺ .

1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde (Intermediate KQ)

Step 1 - 3-(3-methyl-2-oxo-5-vinyl-benzimidazol-1-yl)piperidine-2,6-dione

_A mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine _- 2,6-dione (3.00 g, 8.87 mmol, intermediate J), potassium hydride, trifluoro(vinyl)boron (3.57 g, 26.6 mmol), _Cs2CO3 (2M, 8.87 mL), Pd(dppf) _Cl2.CH2Cl2 (724 mg, 887 umol) in ^dioxane (30 mL) was _degassed and purged with _N2 three times, then the mixture was stirred at 80°C under _N2 atmosphere for 3 h. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (TFA condition) to give the title compound (1.60 g, 58% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 286.0 (M+H) ⁺ .

Step 2 - 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde

To a solution of 3-(3-methyl-2-oxo-5-vinyl-benzimidazol-1-yl)piperidine-2,6-dione (0.30 g, 1.05 mmol) in a mixed solvent of dioxane (20 mL) and H ₂ O (2 mL) was added NaIO ₄ (449 mg, 2.10 mmol), OsO ₄ (267 mg, 1.00 mmol) and NMO (61.0 mg, 525 umol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the residue was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (TFA condition) to give the title compound (0.1 g, 32% yield) as a grey solid. LC-MS (ESI+) m/z 288.0 (M+H) ⁺ .
Example 1 (Method 1): Synthesis of 2-((5-bromo-2-((4-(N-(15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6,9,12-tetraoxapentadecyl)sulfamoyl)-2-methylphenyl)amino)pyrimidin-4-yl)amino)-6-fluorobenzamide (I-37)

^ａこの反応を１時間から２４時間までのいずれかで室温で行った。カップリング生成物の、ｐｒｅｐ－ＨＰＬＣおよび逆相クロマトグラフィーが挙げられる標準的な技術による精製。^ｂＬＣＭＳ ｍ／ｚを［Ｍ－Ｈ］^－として報告する。^ｃＬＣＭＳ ｍ／ｚを［Ｍ－Ｈ_２Ｏ＋Ｈ］^＋として報告する。^ｄＬＣＭＳ ｍ／ｚを［Ｍ＋Ｎａ］^＋として報告する。^ｅＤＩＥＡをＡＣＮ中で塩基として使用し、そしてこの反応を室温で１０分間～２時間行った。^ｆカップリングの生成物を、その後Ｐｄ／Ｃで、ＤＩＥＡまたはＴＥＡを用いて、ＴＨＦ中で水素雰囲気下で、室温で０．５～４０時間水素化した。^ｇ２－Ｍｅ－ＴＨＦを溶媒として使用し、反応物を室温で一晩撹拌した。
実施例２（方法２）：３－（４－（１－（４－（（６－（ジフルオロメチル）－８－（（１Ｒ，２Ｒ）－２－ヒドロキシ－２－メチルシクロペンチル）－７－オキソ－７，８－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）アミノ）ピペリジン－１－イル）－１－オキソ－３，６，９，１２－テトラオキサペンタデカン－１５－イル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－ベンゾ［ｄ］イミダゾール－１－イル）ピペリジン－２，６－ジオン（Ｉ－２１）の合成

To a solution of 3-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (51.3 mg, 0.097 mmol, Intermediate D1) in DCM (5.0 mL) was added Et ₃ N (0.2 mL) and 4-((5-bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride (50 mg, 0.097 mmol, Intermediate L3) and the mixture was stirred at room temperature for 4 h. The mixture was diluted with water (15 mL) and extracted with DCM (30 mL × 3). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10/1, v/v) to give the title compound (25.5 mg, yield 27%) as a white solid. LCMS m/z = 970.4 and 972.4 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.1 (s, 1H), 10.2 (s, 1H), 9.00 (s, 1H), 8.28 (s, 1H), 8.18 - 8.03 (m, 3H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 - 7.54 (m, 3H), 7.32 - 7.23 (m, 1H), 7.02 - 6.92 (m, 3H), 6.91 - 6.83 (m, 1H), 5.35 (dd, J = 12.4, 5.4 Hz, 1H), 3.55 (s, 3H), 3.53 - 3.39 (m, 16H), 2.97 - 2.84 (m, 5H), 2.73 - 2.57 (m, 2H), 2.29 (s, 3H), 2.03 - 1.95 (m, 1H), 1.86 - 1.76 (m, 2H).

^a The reaction was carried out at room temperature for anywhere from 1 to 24 hours. Purification of the coupling products by standard techniques including prep-HPLC and reverse phase chromatography. ^b LCMS m/z is reported as [M-H] ^- . ^c LCMS m/z is reported as [M- _H2O +H] ⁺ . ^d LCMS m/z is reported as [M+Na] ⁺ . ^e DIEA was used as the base in ACN and the reaction was carried out at room temperature for 10 minutes to 2 hours. ^f The coupling products were then hydrogenated on Pd/C with DIEA or TEA in THF under a hydrogen atmosphere at room temperature for 0.5 to 40 hours. ^g 2-Me-THF was used as the solvent and the reaction was stirred at room temperature overnight.
Example 2 (Method 2): Synthesis of 3-(4-(1-(4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-1-oxo-3,6,9,12-tetraoxapentadecan-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (I-21)

^ａ標準的な条件下でのカップリング、カップリング生成物の、ｐｒｅｐ－ＨＰＬＣおよび逆相クロマトグラフィーが挙げられる標準的な技術による精製。^ｂＣＭＰＩ、ＤＩＥＡ、ＤＭＦ中で室温で１．５時間を、カップリングのために使用した。
実施例３（方法３）：［（１Ｒ，３Ｓ）－３－［１－ｔｅｒｔ－ブチル－５－［［５－（メトキシメチル）－２－メチル－ピラゾール－３－カルボニル］アミノ］ピラゾール－３－イル］シクロペンチル］=Ｎ－［７－［１－（２，６－ジオキソ－３－ピペリジル）－３－メチル－２－オキソ－ベンゾイミダゾール－５－イル］ヘプチル］カルバメート（Ｉ－８１）の合成
To a solution of 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (55.8 mg, 0.142 mmol, Intermediate L1) and 15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6,9,12-tetraoxapentadecanoic acid (60 mg, 0.118 mmol, Intermediate A1) in DMF (5 mL) was added Et _N (119.4 mg, 1.18 mmol) and the mixture was cooled to -20 °C. A solution of _T3P 50% in DMF (90.1 mg, 0.142 mmol) was then added and the mixture was stirred at -20°C for 2 h, then allowed to warm to room temperature and stirred overnight. Upon completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with _brine , dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (Model: SHIMADZU preparative HPLC system- equipped with LC-20AP lamp, SPD-20A detector and Labsolutions (version 5.90) software; Column: Agilent 10, Prep-C18, 250 x 21.2 mm. Solvent/gradient: 5-80% acetonitrile in water with 0.1% HCOOH. Flow rate: 20 mL/min) to give the title compound (21.4 mg, 21% yield) as a white solid. LCMS: m/z=883.5[M+H] ⁺ ; ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.9 (s, 1H), 8.76 (s, 1H), 8.10 (s, 2H), 7.05 - 6.68 (m, 4H), 5.69 (s, 1H), 5.32 (dd, J = 12.6, 5.4 Hz, 1H), 4.49 - 3.83 (m, 5H), 3.60 - 3.49 (m, 16H), 3.46 (t, J = 6.0 Hz, 2H), 3.15 - 3.02 (m, 1H), 3.01 - 2.78 (m, 4H), 2.75 - 2.59 (m, 3H), 2.07 - 1.42 (m, 12H), 1.26 (s, 3H).

^a Coupling under standard conditions, purification of the coupling product by standard techniques including prep-HPLC and reverse phase chromatography. ^b CMPI, DIEA, 1.5 h at room temperature in DMF was used for coupling.
Example 3 (Method 3): Synthesis of [(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]=N-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]heptyl]carbamate (I-81)

Step 1 - [(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-[9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]nonyl]carbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl phenyl carbonate (50 mg, 101 umol, Intermediate P), 3-[5-(7-aminoheptyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (56.4 mg, 151 umol, Intermediate BT) and DIEA (65.2 mg, 504 umol) in DMF (0.5 mL) was stirred at 80° C. for 12 h. Upon completion, the mixture was quenched with sat. NH ₄ Cl (5 mL) and extracted with EtOAc (5 mL×2). The combined organic layers were washed with brine (10 mL x 2), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 0/1) to give the title compound ( _0.04 g, 21% yield, 40% purity) as an orange solid. LCMS: tR = 0.680 min, (ES ⁺ ) m/z (M+H) ⁺ = 774.4.

^ａ工程１を、６０℃から８０℃までのいずれかで１２時間～２７時間のいずれかで行った。工程２を、７０～８０℃のいずれかで２～２４時間のいずれかで行った。
実施例４（方法４）：（１Ｒ，３Ｓ）－３－（５－（１－（４－（（（１－（（１－（２，６－ジオキソピペリジン－３－イル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－ベンゾ［ｄ］イミダゾール－４－イル）メチル）ピペリジン－４－イル）（メチル）アミノ）メチル）シクロヘキシル）－１Ｈ－ピラゾール－４－カルボキサミド）－１Ｈ－ピラゾール－３－イル）シクロペンチル=イソプロピルカルバメート（Ｉ－８４）の合成
Step 2 - [(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]=N-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]heptyl]carbamate. A solution of [(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]heptyl]carbamate (0.03 g, 38.8 umol, 40% purity) in HCOOH (1 mL) was stirred for 2 h at 80° C. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA conditions, column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35% to 65%, 10 min) to give the title compound (15 mg, 20.3 umol, 52% yield) as a white solid. LCMS: tR=0.620 min, (ES ⁺ )m/z(M+H) ⁺ =718.3. ^1H NMR (400 MHz, DMSO-d6) δ = 12.41 - 12.09 (br, 1H), 11.07 (s, 1H), 10.90 - 10.56 (br, 1H), 7.11 (s, 1H), 7.04 - 6.99 (m, 2H), 6.97 (s, 1H), 6.84 (br d, J = 8.8 Hz, 1H), 6.40 (br s, 1H), 5.32 (br dd, J = 5.2, 12.4 Hz, 1H), 5.02 - 4.94 (m, 1H), 4.33 (s, 2H), 4.04 (s, 3H), 3.31 (br s, 3H), 3.26 (s, 3H), 3.10 - 3.04 (m, 1H), 2.96 - 2.87 (m, 3H), 2.71 - 2.66 (m, 1H), 2.66 - 2.55 (m, 4H), 2.54 (br s, 1H), 2.03 - 1.97 (m, 2H), 1.89 (br dd, J = 3.6, 6.4 Hz, 1H), 1.77 - 1.69 (m, 2H), 1.57 (br s, 2H), 1.40 - 1.34 (m, 2H), 1.25 (br d, J = 13.2 Hz, 6H).

^Step 1 was carried out at a temperature between 60° C. and 80° C. for 12 to 27 hours. Step 2 was carried out at a temperature between 70° C. and 80° C. for 2 to 24 hours.
Example 4 (Method 4): Synthesis of (1R,3S)-3-(5-(1-(4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-84)

Step 1 - (1R,3S)-3-(1-(tert-butyl)-5-(1-((1r,4S)-4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of [4-[4-[[2-tert-butyl-5-[(1S,3R)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]carbamoyl]pyrazol-1-yl]cyclohexyl]methyl methanesulfonate (40.0 mg, 67.5 umol, Intermediate R) and 3-[3-methyl-4-[[4-(methylamino)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (78.0 mg, 202.44 umol, Intermediate S) in DMF (1 mL) was added Cs ₂ CO ₃ (110 mg, 337 umol) at 20° C. under a stream of nitrogen. The reaction was then stirred at 20-60° C. under a nitrogen atmosphere for 10 hours. Upon completion, the reaction was filtered to obtain the filtrate. The filtrate was purified by prep-HPLC (0.1% FA condition) to give the title compound (10 mg, 17% yield) as a colorless oil: LC-MS (ESI ⁺ ) m/z 882.5 (M+H) ⁺ .

^ａＫ_２ＣＯ_３を工程１で塩基として使用し、これをＭｅＣＮ中で４０℃で１２時間行った。^ｂ工程１を６０℃で１２時間行い、工程２を７５℃で１２時間行った。
実施例５（方法５）：［（１Ｒ，３Ｓ）－３－［５－［［２－［２－［２－［３－［１－（２，６－ジオキソ－３－ピペリジル）－３－メチル－２－オキソ－ベンゾイミダゾール－４－イル］プロポキシ］エトキシ］エチル］ピラゾール－３－カルボニル］アミノ］－１Ｈ－ピラゾール－３－イル］シクロペンチル］=Ｎ－イソプロピルカルバメート（Ｉ－７８）
Step 2 - (1R,3S)-3-(5-(1-(4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A solution of [(1R,3S)-3-[2-tert-butyl-5-[[1-[4-[[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate (10.0 mg, 11.3 umol) in formic acid (0.2 mL) was added at 20° C. under a stream of nitrogen. The reaction was then stirred at 70° C. under a nitrogen atmosphere for 10 hours. Upon completion, the reaction was concentrated to provide a residue. The residue was purified by prep-HPLC (conditions 0.1% FA) to provide the title compound (5 mg, 50% yield) as a colorless oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 10.43 - 10.26 (br s, 1H), 8.37 (br d, J = 5.2 Hz, 2H), 8.12 - 7.96 (m, 1H), 7.09 - 6.85 (m, 3H), 6.36 (s, 1H), 5.63 - 5.43 (m, 1H), 5.00 (br d, J = 4.0 Hz, 1H), 4.29 - 3.98 (m, 2H), 3.68 - 3.60 (m, 8H), 3.11 - 2.93 (m, 3H), 2.90 - 2.72 (m, 4H), 2.65 - 2.55 (m, 1H), 2.41 - 2.34 (m, 3H), 2.17 - 1.54 (m, 18H), 1.38 - 1.22 (m, 2H), 1.20 - 1.09 (m, 2H), 1.03 (br d, J = 6.4 Hz, 6H). LC-MS(ESI ⁺ )m/z 826.3(M+H) ⁺ .

^a _K2CO3 was used as the base in step 1, which was carried out in MeCN at 40 °C for 12 h. ^b Step ₁ was carried out at 60 °C for 12 h and step 2 was carried out at 75 °C for 12 h.
Example 5 (Method 5): [(1R,3S)-3-[5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]-1H-pyrazol-3-yl]cyclopentyl]=N-isopropylcarbamate (I-78)

Step 1 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-[2-(2-prop-2-ynoxyethoxy)ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate (200 mg, 378 umol, Intermediate X) and 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (153 mg, 454 umol, Intermediate H) in THF (1 mL) and ACN (1 mL) was added XPhos Pd G3 (96.1 mg, 113 umol) and Cs ₂ CO ₃ (616 mg, 1.89 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 4 hours. Upon completion, the reaction mixture was quenched with NH ₄ Cl (sat. aq, 5 mL) at 0° C. and then extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-68%, 10 min) to give the title compound (70 mg, 24% yield) as a white solid. LCMS: tR=0.642 min, (ES+) m/z (M+H)+=786.3.

Step 2 - [(1R,3S)-3-[1-tert-butyl-5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (100 mg, 127 umol) and _PtO2 (14.0 mg, 61.7 umol) in THF (2 mL) was placed under an atmosphere of _H2 and stirred at 25 °C for 1 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound (100 mg) as a brown solid.

^ａ工程１を６０℃で４～１２時間行った。工程３を７０～８０℃で２～１２時間行った。種々の条件を用いるｐｒｅｐ ＨＰＬＣを含めた標準的な技術による精製。^ｂ工程２は、水素化（１５ｐｓｉ）室温でＴＨＦ中で１０分間～１２時間を用いるＰｄ／Ｃを利用した。^ｃ工程１で臭化物ではなく塩化物を使用。^ｄ工程２の水素化を省略した。^ｅ工程１は、ＣｕＩ、Ｐｄ（ＰＰｈ_３）_２Ｃｌ_２およびＴＥＡをカップリングのために利用し、そしてこの混合物を６０℃で２時間撹拌した。
実施例６（方法６）：（１Ｒ，３Ｓ）－３－（３－（２－（１－（７－（１－（２，６－ジオキソピペリジン－３－イル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－ベンゾ［ｄ］イミダゾール－４－イル）ヘプチル）－１Ｈ－ピラゾール－４－イル）アセトアミド）－１Ｈ－ピラゾール－５－イル）シクロペンチル=イソプロピルカルバメート（Ｉ－２４７）の合成
Step 3 - [(1R,3S)-3-[5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]-1H-pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate. A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (70 mg, 88.6 umol) in HCOOH (1 mL) was stirred for 2 h at 80° C. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA conditions, column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 28%-58%, 10 min) to give the title compound (20 mg, 30% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.20 (br s, 1H), 11.08 (s, 1H), 10.73 (br s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 6.95 (br d, J = 5.2 Hz, 3H), 6.85 - 6.81 (m, 1H), 6.41 (br s, 1H), 5.35 (br dd, J = 5.2, 12.5 Hz, 1H), 5.04 - 4.95 (m, 1H), 4.70 (t, J = 5.6 Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.61 - 3.54 (m, 1H), 3.52 (s, 3H), 3.50 - 3.42 (m, 4H), 3.38 (br t, J = 6.0 Hz, 2H), 3.09 - 3.00 (m, 1H), 2.92 - 2.87 (m, 2H), 2.85 (br d, J = 5.6 Hz, 1H), 2.75 - 2.61 (m, 2H), 2.46 - 2.41 (m, 1H), 2.04 - 1.96 (m, 2H), 1.91 - 1.84 (m, 1H), 1.80 - 1.70 (m, 4H), 1.64 - 1.57 (m, 1H), 1.02 (d, J = 6.4 Hz, 6H); LC-MS(ESI ⁺ ) m/z 734.3(M+H) ⁺ .

^a Step 1 was carried out at 60° C. for 4-12 hours. Step 3 was carried out at 70-80° C. for 2-12 hours. Purification by standard techniques including prep HPLC using a variety of conditions. ^b Step 2 utilized Pd/C with hydrogenation (15 psi) at room temperature in THF for 10 minutes to 12 hours. ^c Step 1 used chloride rather than bromide. ^d Hydrogenation in step 2 was omitted. ^e Step 1 utilized CuI, Pd(PPh ₃ ) ₂ Cl ₂ and TEA for coupling and the mixture was stirred at 60° C. for 2 hours.
Example 6 (Method 6): Synthesis of (1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (I-247)

Step 1 - (1R,3S)-3-(1-(tert-butyl)-3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of 2-[1-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]heptyl]pyrazol-4-yl]acetic acid (34 mg, 0.07 mmol, Intermediate AV) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (26 mg, 0.08 mmol, Intermediate U) in DMF (1 mL) was added HATU (40 mg, 0.11 mmol) in one portion followed by DIEA (27 mg, 0.21 mmol). The mixture was stirred at 50° C. for 5 h. Upon completion, HCOOH (0.2 mL) was added to the mixture and the mixture was stirred at 20° C. for 0.5 h. The solution was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-68%, 11.5 min) and lyophilized to give the title compound (25 mg, 46% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 772.7 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (25 mg, 0.03 mmol) in HCOOH (2.00 g, 41.63 mmol) was stirred at 80° C. for 12 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 11.5 min) and lyophilized to give the title compound (3 mg, 11% yield) as a yellow gum. LC-MS (ESI ⁺ ) m/z 716.6 (M+H) ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.11-11.95 (m, 1H), 11.09 (br s, 1H), 10.34 (d, J = 3.2 Hz, 1H), 7.56 (s, 1H), 7.30 (s, 1H), 6.99-6.90 (m, 3H), 6.88-6.83 (m, 1H), 6.37-6.21 (m, 1H), 5.36 (dd, _J1 = 12.4 Hz, _J2 = 4.8 Hz, 1H), 5.03-4.93 (m, 1H), 4.03 (t, J = 7.2 Hz, 2H), 3.54 (s, 3H), 3.39 (s, 2H), 3.07-2.97 (m, 1H), 2.91-2.82 (m, 3H), 2.76-2.68 (m, 1H), 2.66-2.58 (m, 1H), 2.04-1.96 (m, 2H), 1.90-1.83 (m, 1H), 1.77-1.67 (m, 4H), 1.64-1.51 (m, 4H), 1.41-1.29 (m, 5H), 1.25-1.20 (m, 2H), 1.02 (d, J = 6.4 Hz, 6H).
Example 7. Synthesis of (1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (I-103)

(1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate was prepared as described in Method 6 from 2-(1-(7-(1-(2, (6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetic acid (Intermediate AY) was synthesized by coupling with (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate U) in step 1. The final compound was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 11.5 min) and lyophilized to give the title compound (11 mg, 34% yield) as a yellow gum. LC-MS(ESI ⁺ )m/z 716.6(M+H) ⁺ ; ^1H NMR (400 MHz, DMSO-d ₆ ) δ = 12.17-11.89 (m, 1H), 11.08 (s, 1H), 10.34 (s, 1H), 7.56 (s, 1H), 7.30 (s, 1H), 7.03-6.97 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.85 (dd, J ₁ = 8.0 Hz, J ₂ = 1.2 Hz, 1H), 6.28 (br s, 1H), 5.33 (dd, J ₁ = 12.8 Hz, J ₂ = 5.2 Hz, 1H), 4.98 (d, J = 2.0 Hz, 1H), 4.02 (t, J = 7.2 Hz, 2H), 3.56 (td, J ₁ = 13.6 Hz, J ₂ = 6.8 Hz, 1H), 3.39 (s, 2H), 3.32 (s, 1H), 3.09-2.97 (m, 1H), 2.96-2.84 (m, 1H), 2.77-2.66 (m, 1H), 2.66-2.56 (m, 3H), 2.49-2.39 (m, 2H), 2.05-1.93 (m, 2H), 1.92-1.81 (m, 1H), 1.77-1.63 (m, 4H), 1.62-1.51 (m, 3H), 1.36-1.15 (m, 7H), 1.02 (d, J = 6.4 Hz, 6H).
Example 8 (Method 7): Synthesis of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide (I-157)

^ａ還元的アミノ化を、ＫＯＡｃを使用される塩基として使用すること、および４Aのモレキュラーシーブを添加することを含めた、標準的な条件下で行った。この反応を、－１０から室温までのいずれかで行い、そして最終生成物を、ｐｒｅｐ－ＨＰＣｌおよびシリカゲルクロマトグラフィーを含めた標準的な技術により精製した。^ｂこの還元的アミノ化の生成物を、Ｐｄ／Ｃで、ＤＩＥＡを用いて、ＴＨＦ中Ｈ_２（１５ＰＳＩ）下で室温で１２時間、さらに水素化した。
実施例９。（１Ｒ，３Ｓ）－３－（５－（１－（４－（（９－（（１－（２，６－ジオキソピペリジン－３－イル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－ベンゾ［ｄ］イミダゾール－４－イル）メチル）－３，９－ジアザスピロ［５．５］ウンデカン－３－イル）メチル）フェニル）－１Ｈ－ピラゾール－４－カルボキサミド）－１Ｈ－ピラゾール－３－イル）シクロペンチル=イソプロピルカルバメート（Ｉ－５３）の合成
To a solution of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide (50 mg, 77.1 umol, TFA, Intermediate DI) in DMF (2 mL) was added TEA (7.81 mg, 77.1 umol) at −10° C. Then 3-[3-methyl-2-oxo-5-(4-oxo-1-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (27.4 mg, 77.1 umol, Intermediate DH) and HOAc (4.63 mg, 77.1 umol) were added at −10° C. and the mixture was stirred for 30 min. Then NaBH(OAc) ₃ (32.7 mg, 154 umol) was added and the mixture was stirred at −10° C. for 2 h. Upon completion, the reaction mixture was quenched with water (0.05 mL) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150×25 mm 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 27%-57%, 8 min) to give the title compound (3.9 mg, 6% yield) as a pale white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.06 (s, 1H), 9.65 (s, 1H), 8.74 (s, 1H), 8.16 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.68 (s, 1H), 7.65 - 7.60 (m, 1H), 7.56 - 7.50 (m, 1H), 6.97 - 6.87 (m, 1H), 6.81 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.69 - 5.56 (m, 1H), 5.28 (dd, J = 4.4, 13.2 Hz, 1H), 3.59 (td, J = 4.0, 6.4 Hz, 2H), 2.87 - 2.74 (m, 4H), 2.71 - 2.64 (m, 3H), 2.63 (s, 2H), 2.59 (s, 3H), 2.34 (s, 6H), 2.29 - 2.13 (m, 5H), 2.04 - 1.92 (m, 2H), 1.88 - 1.75 (m, 2H), 1.61 - 1.48 (m, 4H), 1.41 (d, J = 6.4 Hz, 6H), LC-MS(ESI ⁺ )m/z 874.3(M+H) ⁺ .

^a Reductive amination was carried out under standard conditions including the use of KOAc as the base used and the addition of 4A molecular sieves. The reaction was carried out either at -10 to room temperature and the final product was purified by standard techniques including prep-HPLC and silica gel chromatography. ^b The product of this reductive amination was further hydrogenated over Pd/C with DIEA under H ₂ (15 PSI) in THF at room temperature for 12 hours.
Example 9. Synthesis of (1R,3S)-3-(5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-53)

Step 1 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 3-(4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (37.8 mg, 88.8 umol, intermediate CA) and (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (45 mg, 88.8 umol, intermediate BV) in DMF (1 mL) and THF (1 mL) was added AcOH (16.0 mg, 266 umol), NaBH(OAc) ₃ (37.6 mg, 177 umol) and AcOK (26.1 mg, 266 umol) were added in one portion. The mixture was stirred at 25° C. for 10 h. Upon completion, the resulting mixture was poured into ice water (3 mL) and extracted with ethyl acetate (2×3 mL). The combined organic phase was washed with brine (2×3 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC [Column: Phenomenex Luna C18 150×25 mm×10 um; Mobile phase: [Water (0.225% FA)-ACN]; B%: 9%-39%, 10 min] to give the title compound (10 mg, 10.9 umol, 12% yield) as a yellow oil. LC-MS (ESI+) m/z 458.9 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (10 mg, 10.9 umol) in HCOOH (1 mL) was stirred at 20-80° C. for 1 h. Upon completion, the mixture was concentrated to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 29%-59%, 10 min) to afford the title compound (0.59 mg, 6% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 11.24 - 10.94 (m, 1H), 10.52 (br s, 1H), 9.08 (s, 1H), 8.30 (d, J = 3.6 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.06 (br d, J = 7.5 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.90 - 6.83 (m, 1H), 6.46 - 6.37 (m, 1H), 5.41 - 5.31 (m, 1H), 5.05 - 4.95 (m, 1H), 3.66 (s, 3H), 3.63 - 3.55 (m, 4H), 2.94 - 2.83 (m, 2H), 2.76 - 2.57 (m, 4H), 2.37 - 2.32 (m, 8H), 2.08 - 1.84 (m, 4H), 1.80 - 1.56 (m, 4H), 1.41 (br d, J = 15.5 Hz, 6H), 1.03 (d, J = 6.6 Hz, 6H). LC-MS(ESI+) m/z 860.5(M+H) ⁺ .
Example 10. Synthesis of (1R,3S)-3-(3-(1-(4-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)(methyl)amino)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (I-54)

To a solution of 3-(3-methyl-4-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (38.0 mg, 116 umol, Intermediate BY) in DMF (0.3 mL) and THF (0.3 mL) was added KOAc (30.5 mg, 310 umol), (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (35 mg, 77.7 umol, Intermediate BW) _and NaBH(OAc) (32.9 mg, 155 umol) in one portion at 0° C. The mixture was stirred at 0-25° C. for 10 hours. The mixture was poured into ice water (3 mL) and extracted with ethyl acetate (2×3 mL). The combined organic phase was washed with brine (2×3 mL) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10 min) to give the title compound (8.17 mg, 10.7 umol, 14% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.21 - 12.11 (m, 1H), 11.12 - 11.08 (m, 1H), 10.52 (s, 1H), 9.11 - 9.07 (m, 1H), 8.30 (s, 1H), 7.83 - 7.81 (m, 2H), 7.51 - 7.49 (m, 2H), 7.17 - 6.95(m, 4H), 6.42 (s, 1H), 5.42 - 5.36 (m, 1H), 5.01 - 4.99 (m, 1H), 3.69 (s, 3H), 3.67 -3.60 (m, 4H), 3.20-2.65 (m, 6H), 2.33 (s, 3H), 2.13 (s, 1H), 2.04-1.72 (m, 6H), 1.03 (d, J = 6.4 Hz, 6H). LC-MS(ESI+) m/z 761.4(M+H) ⁺ .
Example 11. Synthesis of (1R,3S)-3-(5-(1-(2-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-56)

A solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (25 mg, 30.8 umol, synthesized by step 1 of method 5) in formic acid (0.5 mL) was stirred at 70° C. under nitrogen atmosphere for 10 hours. Upon completion, the reaction was concentrated to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 min) and lyophilized to give the title compound (1.56 mg, 7% yield) as a yellow gum. ^1H NMR (400 MHz, DMSO- _d6 ) δ = 12.36 - 12.15 (m, 1H), 11.11 (br d, J = 4.8 Hz, 1H), 10.75 (br s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 - 7.05 (m, 2H), 7.03 - 6.97 (m, 1H), 6.94 (br d, J = 6.8 Hz, 1H), 6.44 - 6.36 (m, 1H), 5.38 (dd, J = 5.2, 12.5 Hz, 1H), 4.99 (br d, J = 5.6 Hz, 1H), 4.62 (br t, J = 6.4 Hz, 2H), 3.64 - 3.53 (m, 4H), 3.49 (s, 2H), 3.17 - 2.83 (m, 6H), 2.77 - 2.56 (m, 6H), 2.35 - 2.29 (m, 2H), 2.06 - 1.97 (m, 2H), 1.89 (br d, J = 6.8 Hz, 5H), 1.02 (d, J = 6.4 Hz, 6H). LC-MS(ESI ⁺ )m/z 754.4(M+H) ⁺ .
Example 12. Synthesis of (1R,3S)-3-(5-(1-(9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)non-8-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-86)

A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-[9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]non-8-ynyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate (0.07 g, 89.5 umol, synthesized by step 1 of method 5) in HCOOH (0.5 mL) was stirred at 80° C. for 2 hours. Upon completion, the mixture was concentrated in vacuo and purified by prep-HPLC (FA conditions, column: 3_Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 42%-72%, 10 min) to afford the title compound (12 mg, 17% yield) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 7.50 (d, J = 2.0 Hz, 1H), 7.13 (br s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.06 - 7.03 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.97 - 6.92 (m, 1H), 6.42 (br s, 1H), 5.39 (dd, J = 5.2, 12.8 Hz, 1H), 5.03 - 4.97 (m, 1H), 4.52 (br t, J = 7.2 Hz, 2H), 3.63 (s, 3H), 3.58 (br dd, J = 6.4, 14.0 Hz, 1H), 3.12 - 3.04 (m, 1H), 2.93 - 2.84 (m, 1H), 2.76 - 2.65 (m, 2H), 2.35 - 2.31 (m, 1H), 2.05 - 2.00 (m, 2H), 1.89 (dt, J = 2.8, 6.8 Hz, 1H), 1.77 - 1.70 (m, 4H), 1.67 - 1.61 (m, 1H), 1.58 - 1.51 (m, 2H), 1.41 - 1.23 (m, 7H), 1.03 (d, J = 6.5 Hz, 6H).
Example 13. Synthesis of (1R,3S)-3-(5-(1-(12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodeca-11-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-88)
A solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 60.7 umol, synthesized by step 1 of method 5) in HCOOH (2 mL) was stirred at 70° C. for 12 hours. Upon completion, the mixture was concentrated under reduced pressure to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 62%-92%, 1.5 min) and lyophilized to give the title compound (12.7 mg, 25% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO-d6) δ 12.23 (br s, 1H), 11.10 (br s, 1H), 10.69 (br s, 1H), 7.48 (s, 1H), 7.25 - 6.81 (m, 5H), 6.41 (br s, 1H), 5.38 (br dd, J = 5.2, 12.6 Hz, 1H), 5.00 (br d, J = 3.6 Hz, 1H), 4.49 (br t, J = 6.8 Hz, 2H), 3.72 - 3.49 (m, 3H), 3.14 - 3.02 (m, 1H), 2.96 - 2.82 (m, 1H), 2.77 - 2.57 (m, 2H), 2.47 - 2.40 (m, 4H), 2.08 - 1.96 (m, 3H), 1.93 - 1.84 (m, 1H), 1.78 - 1.65 (m, 4H), 1.60 - 1.51 (m, 2H), 1.46 - 1.35 (m, 2H), 1.34 - 1.17 (m, 10H), 1.03 (br d, J = 6.4 Hz, 6H). LC-MS(ESI+) m/z 768.4(M+H) ⁺ .
Example 14. Synthesis of (1R,3S)-3-(5-(1-(11-(3-(2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidin-2-yl)thiazole-4-carbonyl)phenoxy)undecyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-148)

Step 1 - ((S)-1-(((S)-2-((S)-2-(4-(3-((11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl. To a solution of 11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl 4-methylbenzenesulfonate (100 mg, 68.7 umol, intermediate ET) and tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (49.4 mg, 82.5 umol, intermediate ER) in DMF (2 mL) was added KI (1.14 mg, 6.88 umol) and Cs ₂ CO ₃ (67.2 mg, 206 umol) was added. The mixture was then stirred at 70° C. for 2 h. Upon completion, the reaction mixture was quenched with aqueous NaHCO ₃ (2 mL) at 20° C., then diluted with 1 mL of EtOAc and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (2 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate=0:1) to give the title compound (20 mg, 25% yield) as a brown solid.

Step 2 - (1R,3S)-3-(5-(1-(11-(3-(2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidin-2-yl)thiazole-4-carbonyl)phenoxy)undecyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of tert-butyl ((S)-1-(((S)-2-((S)-2-(4-(3-((11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (20 mg, 17.3 umol) in DCE (0.5 mL) was added TFA (154 mg, 1.35 mmol, 0.1 mL) and the mixture was then stirred at 80° C. for 12 h. Upon completion, it was filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (Column: Phenomenex Luna C18 150×25 mm×10 um; Mobile phase: [Water (0.225% FA)-ACN]; B%: 34%-64%, 10 min) to give the title compound (3.89 mg, 23% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 12.32 - 11.83 (m, 1H), 10.33 (br s, 1H), 8.51 - 8.43 (m, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.98 - 7.88 (m, 1H), 7.68 - 7.58 (m, 2H), 7.48 - 7.42 (m, 1H), 7.25 - 7.19 (m, 1H), 6.95 (br d, J = 6.8 Hz, 1H), 6.36 (br s, 1H), 5.42 - 5.34 (m, 1H), 4.99 (br d, J = 2.8 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.10 (t, J = 6.8 Hz, 2H), 4.01 (br t, J = 6.4 Hz, 3H), 3.84 - 3.76 (m, 1H), 3.71 - 3.63 (m, 1H), 3.55 (br dd, J = 7.6, 14.0 Hz, 2H), 3.09 - 2.99 (m, 2H), 2.99 - 2.92 (m, 1H), 2.29 - 2.23 (m, 1H), 2.22 - 2.12 (m, 3H), 2.09 (s, 2H), 2.05 - 1.96 (m, 3H), 1.92 - 1.85 (m, 1H), 1.73 (br dd, J = 6.4, 13.1 Hz, 8H), 1.60 (br s, 4H), 1.55 - 1.48 (m, 1H), 1.45 - 1.38 (m, 2H), 1.24 (br s, 10H), 1.20 - 1.12 (m, 3H), 1.11 - 1.05 (m, 4H), 1.02 (br d, J = 6.4 Hz, 6H), 0.96 - 0.89 (m, 1H). LC-MS(ESI+) m/z 997.6(M+H) ⁺ .
Example 15. Synthesis of 4-[[5-amino-1-(3-methylthiophene-2-carbonyl)-1,2,4-triazol-3-yl]amino]-N-[2-[[1-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl]triazol-4-yl]methoxy]ethyl]benzenesulfonamide (I-136)

To a solution of 3-[5-[3-(2-azidoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (70 mg, 200 umol, Intermediate FD) and 4-[[5-amino-1-(3-methylthiophene-2-carbonyl)-1,2,4-triazol-3-yl]amino]-N-(2-prop-2-ynoxyethyl)benzenesulfonamide (83.4 mg, 181 umol, Intermediate EE) in DMF (1 mL) was added CuSO ₄ (14.5 mg, 90.6 umol), sodium (2R)-2-[(2R)-3,4-dihydroxy-5-oxo-2H-furan-2-yl]-2-hydroxy-ethanolate (108 mg, 543 umol, VCNa), t-BuOH (0.9 mL) and H ₂ O (0.1 mL) were added at 20° C. under nitrogen flow. The reaction was then stirred at 70° C. under nitrogen atmosphere for 2 hours. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (Column: Phenomenex Luna C18 100×30 mm×5 um; Mobile phase: [Water (0.225% FA)-ACN]; B%: 30%-60%, 8 min) to give the title compound (58 mg, 37% yield) as a white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 11.08 (br s, 1H), 9.94 (s, 1H), 8.06 - 8.02 (m, 2H), 7.91 - 7.79 (m, 4H), 7.76 - 7.70 (m, 2H), 7.51 - 7.43 (m, 1H), 7.16 (d, J = 5.2 Hz, 1H), 7.01 - 6.91 (m, 2H), 6.79 (dd, J = 1.6, 8.0 Hz, 1H), 5.33 (dd, J = 5.2, 12.8 Hz, 1H), 4.54 - 4.49 (m, 2H), 4.47 (s, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.45 - 3.40 (m, 2H), 3.38 (br s, 4H), 3.31 (s, 3H), 2.91 - 2.86 (m, 2H), 2.76 - 2.65 (m, 1H), 2.63 (s, 3H), 2.57 - 2.52 (m, 2H), 2.04 - 1.95 (m, 1H), 1.81 - 1.68 (m, 2H); LC-MS(ESI+)m/z 847.4(M+H) ⁺ .
Example 16. Synthesis of 3-[4-[7-[4-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-1-piperidyl]sulfonyl]pyrazol-1-yl]heptylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (I-165)

Step 1 - 3-[4-(7-bromoheptylamino)-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. To a solution of 3-[4-(7-bromoheptylamino)-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (24.0 mg, 41.9 umol, Intermediate JZ) and 6-chloro-8-isopropyl-2-[[1-(1H-pyrazol-4-ylsulfonyl)-4-piperidyl]amino]pyrido[2,3-d]pyrimidin-7-one (18.9 mg, 41.9 umol, Intermediate KB) in DMF (2 mL) was added K ₂ CO ₃ (29.0 mg, 209 umol) and KI (6.97 mg, 41.9 umol). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (1 mL) at 25 °C. The mixture was then filtered and partitioned between EA (10 mL) and water (10 mL). The organic layer was collected and the aqueous layer was extracted with EA (2×8 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (35 mg, 88% yield) as a white solid. LCMS (ESI ⁺ ) m/z 942.5 (M+H) ⁺ .

Step 2 - 3-[4-[7-[4-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-1-piperidyl]sulfonyl]pyrazol-1-yl]heptylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione. To a solution of 3-[4-[7-[4-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-1-piperidyl]sulfonyl]pyrazol-1-yl]heptylamino]-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (30.0 mg, 31.8 umol) in TFA (1.6 mL) was added TfOH (0.2 mL). The mixture was stirred at 70° C. for 2 hours. Upon completion, the mixture was concentrated in vacuo to give a residue. To the residue was added ACN (1 mL) and TEA at 25° C. until pH=6. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 9 min) to give the title compound (19.2 mg, 69% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.06 (s, 1H), 8.57 (s, 1H), 8.45 - 8.36 (m, 1H), 8.11 - 7.74 (m, 3H), 6.84 (t, J = 8.0 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.83 - 5.58 (m, 1H), 5.28 (dd, J = 5.2, 12.4 Hz, 1H), 4.20 (t, J = 6.8 Hz, 2H), 3.89 - 3.67 (m, 2H), 3.59 (s, 3H), 3.01 (t, J = 7.2 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.75 - 2.67 (m, 1H), 2.66 - 2.58 (m, 2H), 2.46 (s, 2H), 2.40 (d, J = 12.4 Hz, 1H), 2.02 - 1.91 (m, 3H), 1.87 - 1.79 (m, 2H), 1.73 - 1.53 (m, 5H), 1.48 (d, J = 6.8 Hz, 6H), 1.35 (d, J = 2.4 Hz, 4H), 1.25 - 1.19 (m, 2H). LCMS(ESI ⁺ )m/z 822.4(M+H) ⁺ .
Example 17. Degradation assay Degradation of CDK2 and CDK1 by immunoblotting

The ovarian cancer cell line OVCAR-8 was cultured in complete growth medium in 12-well plates. Serial dilutions of each compound were added to individual wells from 2× stock solutions and the cells were cultured for 24 hours. Cells were collected by centrifugation and cell pellets were lysed by the addition of chilled RIPA buffer supplemented with protease/phosphatase inhibitors followed by incubation on ice for 20 minutes. Lysates were cleared by centrifugation and 5× SDS loading buffer was added to the supernatant followed by heating to 100° C. for 10 minutes. Aliquots of samples were resolved by SDS-PAGE and transferred to nitrocellulose membranes. Immunoblotting was performed using anti-CDK2 primary antibody (Abcam ab32147) at a dilution of 1:1000, and IRDye 800CW goat anti-rabbit secondary antibody (LICOR) according to standard procedures and imaged using a LICOR Odyssey instrument. Blots were stained with anti-β-actin primary antibody (Cell Signaling Technology mAb #4970) for normalization. Normalized CDK2/actin values were calculated as a percentage of cells treated with DMSO and plotted to determine the concentration at which 50% of the CDK2 signal is reduced (DC50). CDK1 degradation was determined similarly using anti-CDK1 primary antibody (Abcam ab131450).
Degradation of CCNE1 in MKN-1 cells

Gastric cancer cell line MKN-1 was cultured in complete growth medium in 6-well plates. Serial dilutions of each compound were added to individual wells from 2x stock solutions and cells were cultured for 24 hours. After 24 hours of incubation, cells were lysed by addition of chilled RIPA buffer supplemented with protease/phosphatase inhibitors followed by incubation on ice for 20 minutes. Lysates were cleared by centrifugation and 5x SDS loading buffer was added to the supernatant followed by heating to 100°C for 10 minutes. Aliquots of samples were separated by SDS-PAGE and transferred to nitrocellulose membranes. Immunoblotting was performed using anti-CCNE1 primary antibody (Abcam #ab33911) at a dilution of 1:1000, and IRDye 800CW goat anti-rabbit secondary antibody (LICOR) according to standard procedures, and imaged using a LICOR Odyssey instrument. Blots were stained with anti-β-actin primary antibody (Cell Signaling Technology mAb #3700) for normalization. Normalized CCNE1/actin values were calculated as a percentage of cells treated with DMSO and plotted to determine the concentration at which 50% of the CCNE1 signal was reduced.

CDK2, CDK1, and CCNE1 DC50 results for compounds of the invention are reported in Table 10. Letter codes for DC50 and IC50 include: A (<0.01 μM), B (0.01-0.1 μM), C (>0.1-1.0 μM), D (>1.0-5.0 μM), and E (>5.0 μM).

While the inventors have described several embodiments of the invention, it is apparent that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be understood that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims (28)

Formula I:

or a pharma- ceutically acceptable salt thereof, wherein in formula I:
The CBM is a CDK binding moiety capable of binding to the CDK2 protein, and the compound of formula I has the formula I-a:

or a pharma- ceutically acceptable salt thereof, wherein in formula I-a:
R ^a and R ^b are independently hydrogen or R ^A , or R ^a and R ^b together with the nitrogen to which they are attached form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring W, Ring X, and Ring Y are independently rings selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . selected from -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ^x is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are optionally replaced independently by -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1;
w, x, y, and z are independently 0, 1, 2, 3, or 4;
L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C _1-50 hydrocarbon chain, where the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

has been replaced by:
Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted divalent ring selected from 8-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-membered to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and DIM is a cleavage-inducing moiety, where DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.
A compound or a pharma- ceutically acceptable salt thereof. Formula I:

or a pharma- ceutically acceptable salt thereof, wherein in formula I:
The CBM is a CDK binding moiety capable of binding to the CDK2 protein, and the compound of formula I has the formula I-b:

or a pharma- ceutically acceptable salt thereof, in formula I-b:
Ring W and Ring X are independently a fused ring selected from benzo, 4- to 7-membered saturated or partially unsaturated, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Y is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R; or two R ^w groups attached to the same carbon atom optionally join together to form a spiro-fused ring selected from 3- to 5-membered saturated or partially unsaturated carbocyclyl, and 3- to 5-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen optionally taken together with the atoms between them form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L ^x is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain in which one to two methylene units of the chain are optionally replaced independently with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1;
w, x, y, and z are independently 0, 1, 2, 3, or 4;
L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C _1-50 hydrocarbon chain, where the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

has been replaced by:
Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted divalent ring selected from 8-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-membered to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and DIM is a cleavage-inducing moiety, where DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.
A compound or a pharma- ceutically acceptable salt thereof. Formula I:

or a pharma- ceutically acceptable salt thereof, wherein in formula I:
The CBM is a CDK binding moiety capable of binding to the CDK2 protein, and the compound of formula I has the formula I-c:

or a pharma- ceutically acceptable salt thereof, in formula I-c:
Ring W, Ring X, and Ring Y are independently rings selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . selected from -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ^x is a covalent bond or a C _1-3 divalent linear or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1;
w, x, y, and z are independently 0, 1, 2, 3, or 4;
L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C _1-50 hydrocarbon chain, where the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

has been replaced by:
Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted divalent ring selected from 8-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-membered to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and DIM is a cleavage-inducing moiety, where DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.
A compound or a pharma- ceutically acceptable salt thereof. Formula I:

or a pharma- ceutically acceptable salt thereof, wherein in formula I:
The CBM is a CDK binding moiety capable of binding to the CDK2 protein, and the compound of formula I has the formula I-d:

or a pharma- ceutically acceptable salt thereof, in formula I-d:
R ^a and R ^b are independently hydrogen or R ^A , or R ^a and R ^b together with the nitrogen to which they are attached form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring W is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring X is a bicyclic ring selected from naphthyl, a 9- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NROR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) _{2 .} selected from -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R;
Each R is independently hydrogen or an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ^x is a covalent bond or a C _1-3 divalent linear or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1;
w, x, and z are independently 0, 1, 2, 3, or 4;
L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C _1-50 hydrocarbon chain, where the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

has been replaced by:
Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted divalent ring selected from 8-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-membered to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and DIM is a cleavage-inducing moiety, where DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.
A compound or a pharma- ceutically acceptable salt thereof. Formula I:

or a pharma- ceutically acceptable salt thereof, wherein in formula I:
The CBM is a CDK binding moiety capable of binding to the CDK2 protein, and the compound of formula I has the formula I-e:

or a pharma- ceutically acceptable salt thereof, in formula I-e:
Ring W and Ring X are independently a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Y is a ring selected from phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic, carbocyclyl, or heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ^w , R ^x , R ^y , and R ^z are independently hydrogen, R ^A , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)NR OR, —CR ₂ NRC(O)R, —CR ₂ NRC(O)NR ₂ , —OC(O)R, —OC(O)NR ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ . -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ , and -NRS(O) ₂ R; or two R ^w groups attached to the same carbon atom optionally join together to form a spiro-fused ring selected from 3- to 5-membered saturated or partially unsaturated carbocyclyl, and 3- to 5-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ^A is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen optionally taken together with the atoms between them form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L ^x and L ^y are independently a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain in which one to two methylene units of the chain are optionally replaced independently with -O-, -C(O)-, -C(S)-, -CF ₂ -, -CRF-, -NR-, -S-, -S(O)-, -S(O) ₂ -, or -CR═CR-;
v is 0 or 1;
w, x, y, and z are independently 0, 1, 2, 3, or 4;
L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C _1-50 hydrocarbon chain, where the 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

has been replaced by:
Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted divalent ring selected from 8-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-membered to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and DIM is a cleavage-inducing moiety, where DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.
A compound or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 5, wherein the LBM is a cereblon E3 ubiquitin ligase binding portion, a VHL E3 ubiquitin ligase binding portion, an IAP E3 ubiquitin ligase binding portion, or an MDM2 E3 ubiquitin ligase binding portion. The LBM is a cereblon E3 ubiquitin ligase binding moiety and the compound has the formula I-nn-1:

or a pharma- ceutically acceptable salt thereof, wherein in formula I-nn-1:
Each of X ¹ , X ² , and X ³ independently represents a covalent bond, —CH ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic;
each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R;
Ring A is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclyl, a 5- to 7-membered partially saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0, 1, 2, 3 or 4;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally taken together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Compound. The LBM is a cereblon E3 ubiquitin ligase binding moiety and the compound has the formula I-aa:

or a pharma- ceutically acceptable salt thereof, wherein in formula I-aa:
X ¹ is a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
^X2 is a carbon atom or a silicon atom;
X ³ is a divalent moiety selected from -CR ₂ -, -NR-, -O-, -S-, or -SiR ₂ -;
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, optionally together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ , or an optionally substituted C _1-4 aliphatic;
Each R ² is independently hydrogen, R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) _. -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R, -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)(NR ₂ ) ₂ , or -N(R)S(O) ₂ R;
Ring A is

wherein Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered to 7-membered saturated or partially unsaturated carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R ³ is selected from hydrogen, halogen, —OR, —N(R) ₂ , or —SR;
each R ⁴ is independently hydrogen, —R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —OC(O)R, —OC(O)NR ₂ , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR ₂ , or —N(R)S(O) ₂ R;
^R5 is hydrogen, _C1-4 aliphatic, or -CN;
each R ⁶ is independently an optionally substituted group selected from a C _1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated, carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S(O) ₂ -, or -(C)═CH-; and m is 0, 1, 2, 3, or 4.
Compound. The compound has the following formula:

or a pharma- ceutically acceptable salt thereof. The LBM is a cereblon E3 ubiquitin ligase binding moiety and the compound has the formula I-nn:

or a pharma- ceutically acceptable salt thereof, wherein in formula I-nn:
Ring M is

Selected from:
Each of X ¹ , X ⁶ and X ⁷ independently represents a covalent bond, —CH ₂ —, —CHCF ₃ —, —SO ₂ —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR ₂ —, —C(O)—, —C(S)—, or
is a divalent moiety selected from
Each of ^X3 and ^X5 is independently a divalent moiety selected from a covalent bond, _-CR2- , -NR-, -O-, -S-, or _-SiR2- ;
^X4 is

is a trivalent moiety selected from
Each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R ^3a is independently hydrogen, R ⁶ , halogen, —CN, —NO ₂ , —OR, —SR, —NR ₂ , —SiR ₃ , —S(O) ₂ R, —S(O) ₂ NR ₂ , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR ₂ , —C(O)N(R)OR, —C(R) ₂ N(R)C(O)R, —C(R) ₂ N(R)C(O)N(R) ₂ , —OC(O)R, —OC(O)N(R) ₂ , —OP(O)R ₂ , —OP(O)(OR) ₂ , —OP(O)(OR)NR ₂ , —OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -NP(O) _R2 , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR) _NR2 , -N(R)P(O)( _NR2 ) ₂ , or -N(R)S(O) _2R ;
each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R ⁷ is independently hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH)R ₂ , -Si(OH) ₂ R, -SiR ₃ , or an optionally substituted C _1-4 aliphatic; or R ⁷ and X ¹ or X ³ together with the atoms therebetween form a 5-7 membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
two R ⁷ groups on the same carbon optionally taken together with the atoms between them form a 3- to 6-membered spiro-fused or 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
two R ⁷ groups on adjacent carbon atoms optionally taken together with the atoms between them form a 3- to 7-membered, saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered, saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
Ring D is selected from a 6- to 10-membered aryl, or heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L ¹ is a covalent bond or a C _1-3 divalent straight or branched, saturated or unsaturated hydrocarbon chain, in which one to two methylene units of the chain are independently optionally replaced with -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)═CH-;
n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.
Compound. The compound has the following formula:

or a pharma- ceutically acceptable salt thereof. The LBM is a VHL E3 ubiquitin ligase binding moiety and the compound has the following formula:
(i)

or a pharma- ceutically acceptable salt thereof, wherein each of the variables ^R1 , ^R2 , ^R3 , X, and Y are as defined and described in WO 2019/084026;
(ii)

or a pharma- ceutically acceptable salt thereof, wherein each of the variables ^R1 , ^R3 , and Y are as defined and described in WO 2019/084030;
(iii)

or a pharma- ceutically acceptable salt thereof, wherein each of the variables R1 ^' , R2 ^' , R3 ^' , X, and X' are as defined and described in WO 2013/106643 and US 2014/0356322;
(iv)

or a pharma- ceutically acceptable salt thereof, wherein each of the variables R1 ^' , R2 ^' , R3 ^' , _R5 , _R6 , R7, _R9 , _R10 , _R11 , _R14 , _R15 , _R16 , _R17 , _R23 , _R25 , E, _G , M, X, X', Y, _Z1 , _Z2 , _Z3 , _Z4 , and o are as defined and described in WO 2016/149668 and US 2016/0272639; and

or a pharma- ceutically acceptable salt thereof, wherein each of the variables ^Rp , _R9 , _R10 , R11, _R14a , _R14b , _R15 , _R16 , _W3 , ^W4 , ^W5 , ^{X1 , X2} , and o are as defined and described in WO 2016/118666 and US 2016/0214972;
The compound according to claim 6, selected from any one of the VHL E3 ubiquitin ligase binding moiety

13. The compound according to claim 6 or claim 12, selected from: wherein the LBM is an IAP E3 ubiquitin ligase binding moiety and the compound has the following formula:
(i)

or a pharma- ceutically acceptable salt thereof, wherein each of the variables ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , and ^R7 are as defined and described in WO 2017/011590 and US 2007/037004; and (ii)

or a pharma- ceutically acceptable salt thereof, wherein each of the variables W, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , and ^R5 are as described and defined in WO 2014/044622, US 2015/0225449, WO 2015/071393, and US 2016/0272596;
7. The compound of claim 6, wherein the compound is selected from any one of the following: the IAP E3 ubiquitin ligase binding moiety

15. The compound according to claim 6 or claim 14, selected from: The LBM is an MDM2 E3 ubiquitin ligase binding moiety and the compound has the following formula:
(i)

or a pharma- ceutically acceptable salt thereof, wherein the variables _R1 , _R2 , _R3 , _R4 , R5, _R6 , _R7 , R8, R9, R10, R11, _{R12, R13} , _R14 , _R15 , _R16 , _R17 , _R18 , _R19 , _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _{R1', R2' , R3' , R4 ' ,} R5 _' , R6 _' , _{R7' , R8' , R9' ,} R10 _' , _{R11' ,} R12 _' , _R1'' each of A, A', A'', X, Y, and Z is as defined and described in WO 2017/011371 and US 2017/008904; and (ii)

or a pharma- ceutically acceptable salt thereof, wherein ^{each of the variables R12c, R12d, R13, R17, R18b, R18c, R18d , A5 , A6 , A7 , Q1 , and} Ar are as defined and described in WO 2017/176957 and US2019/127387;
7. The compound of claim 6, wherein the compound is selected from any one of the following: the MDM2 E3 ubiquitin ligase binding portion

17. The compound of claim 6 or claim 16, selected from: 18. The compound of _{any one of claims 1 to 17, wherein L is a covalent bond or a divalent, saturated or partially unsaturated, straight or branched C 1-20} hydrocarbon chain, where 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) _2- , -N(R)S(O) _2- , -S(O) _2N (R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-. The compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds depicted in Table 1. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The pharmaceutical composition of claim 20, further comprising an additional therapeutic agent. A method for inhibiting or degrading CDK2 in a patient or a biological sample, comprising administering to the patient or contacting with the biological sample a compound according to any one of claims 1 to 19, or a pharmaceutical composition thereof. A method of treating a disorder, disease, or condition mediated by CDK2 in a patient, comprising administering to the patient a compound according to any one of claims 1 to 19, or a pharmaceutical composition thereof. 24. The method of claim 23, wherein the disorder, disease, or condition mediated by CDK2 is cancer. 25. The method of claim 24, wherein the cancer is characterized by amplification or overexpression of CCNE1. Use of a compound according to any one of claims 1 to 19, or a pharmaceutical composition thereof, in the manufacture of a medicament in a method for treating a disorder, disease, or condition mediated by CDK2 in a patient, the method comprising administering the compound or composition to the patient. 27. The use of claim 26, wherein the disorder, disease, or condition mediated by CDK2 is cancer. The use of claim 27, wherein the cancer is characterized by amplification or overexpression of CCNE1.